Activin type 2 receptor-binding protein and use thereof

Abstract

Activin receptor type II (ActRII) - binding proteins, and compositions and methods for making ActRII-binding proteins are provided.SOLUTION: To provide isolated ActRII-binding proteins having specific sequences and binding to activin receptor type IIB (ActRIIB) or ActRIIB and activin receptor type IIA (ActRIIA). In certain aspects, the ActRII-binding protein inhibits or antagonizes ActRII activity. In addition, the disclosure provides compositions and methods of diagnosing and treating diseases and conditions associated with muscle wasting; fibrotic conditions; inflammatory, cardiovascular, pulmonary, musculoskeletal, neurological, ocular, skeletal, autoimmune, or metabolic diseases or conditions; wound healing; and cancer, and other ActRII-mediated diseases and conditions.SELECTED DRAWING: Figure 6

Description

[Technical Field]

[0001] Reference to an electronically submitted sequence listing The contents of the Sequence Listing, submitted electronically as ASCII text file 3174_003PC01_SeqListing.txt (size: 177 kilobytes; and created on March 10, 2017) filed herewith, are incorporated herein by reference in their entirety. [Background technology]

[0002] The transforming growth factor-β (TGF-β) family includes a variety of growth factors known to exert biological effects on numerous cell types in both vertebrates and invertebrates. Members of the TGF-β family exert important functions during embryonic development in pattern formation and tissue specification and can influence a variety of differentiation processes, including adipogenesis, myogenesis, chondrogenesis, cardiogenesis, hematopoiesis, neurogenesis, and epithelial cell differentiation. The family includes proteins variously described as growth differentiation factors (GDFs), bone morphogenetic proteins (BMPs), activins, and inhibins.

[0003] TGF-β family members signal through a multistep mechanism in which they bind to type II serine / threonine kinase receptors expressed on the cell surface, the type II receptors form heterologous complexes with their cognate type I receptors, and activate the type I receptors via phosphorylation. The activated type I receptors then phosphorylate and activate Smad proteins, which transmit signals from the cytoplasm to the nucleus, where nuclear Smad oligomers bind to DNA and associate with transcription factors to regulate target gene expression.

[0004] Two related type II TGF-β receptor family members, ActRIIB and ActRIIA, have been identified as type II receptors for activin A and activin B, as well as other TGF-β family members (e.g., BMP7, BMP9, BMP10, GDF1, GDF3, GDF8 (myostatin), GDF11, and Nodal) (Yamashita et al., J. Cell Biol. 130:217-226 (1995); Lee et al., PNAS 98:9306-9311 (2001); Yeo et al., Mol. Cell 7:949-957 (2001); and Oh et al., Genes Dev. 16:2749-54 (2002)). ALK4 and ALK7 are the primary type I TGF-β receptor family member receptors for activin A and activin B, respectively.

[0005] Altered expression and activity of members of the TGF-β ligand and receptor family have been proposed to be associated with a variety of disorders and conditions, including muscle, bone, neurological, and metabolic disorders and conditions, as well as cancer. An object of the present disclosure provides ActRII antagonists and their uses in the diagnosis and treatment, prevention, and / or amelioration of diseases or conditions associated with ActRII and / or ActRII ligands. Summary of the Invention

[0006] The present disclosure provides activin receptor type II (ActRII) binding proteins and methods of using the ActRII binding proteins. In certain aspects, the ActRII binding proteins can inhibit or block the binding of ActRII to one or more cognate ActRII ligands and / or one or more cognate ActRII receptors. In some aspects, the ActRII binding proteins can inhibit or block the binding of ActRII to an ActRII ligand (e.g., activin A, activin B, GDF1, GDF3, GDF8 (myostatin), GDF11, BMP6, BMP7, BMP9, or BMP10). The present disclosure also provides methods of using the ActRII binding proteins for the diagnosis, or treatment, prevention, and / or amelioration of diseases or conditions associated with ActRII expression and / or elevated ActRII-mediated signaling. Such diseases or conditions include, but are not limited to, muscle disorders, such as degenerative muscle diseases, muscular dystrophies, muscle atrophy, or muscle wasting disorders; fibrotic conditions; inflammatory, autoimmune, cardiovascular, pulmonary, musculoskeletal, skeletal, ocular, neurological, or metabolic diseases or conditions; obesity; wound healing; and cancer.

[0007] In some embodiments, the ActRII binding protein specifically binds to ActRIIB. In a further aspect, the provided ActRII binding proteins specifically bind to ActRIIB and have at least one characteristic selected from the group consisting of: (a) compete with an ActRII ligand (e.g., activin A, activin B, GDF1, GDF3, GDF8 (myostatin), GDF11, BMP6, BMP7, BMP9, or BMP10) for binding to ActRIIB; (b) reduce phosphorylation of ALK4 and / or ALK7 in cells expressing ActRIIB and ALK4 and / or ALK7 in the presence of an ActRIIB ligand (e.g., activin A and / or GDF8 (myostatin)); (c) reduce phosphorylation of Smads (e.g., Smad2 and / or Smad3) in cells expressing ActRIIB in the presence of an ActRIIB ligand (e.g., activin A and / or GDF8); and (d) a K of ≦1 nM and ≧1 pM. D (e.g., as determined by BIACORE® analysis) binds to ActRIIB. In some embodiments, the ActRIIB-binding protein has two, three, or four of the above characteristics. In some embodiments, the ActRIIB-binding protein has at least two or at least three of the above characteristics. In a further embodiment, the ActRIIB-binding protein competes for binding to ActRIIB with an antibody having an ActRIIB-binding VH and VL pair disclosed herein. In a further embodiment, the ActRIIB-binding protein is an anti-ActRIIB antibody or an ActRIIB-binding antibody fragment.

[0008] In some embodiments, the ActRII binding protein specifically binds to ActRIIB and ActRIIA. In further embodiments, the provided ActRII binding protein specifically binds to ActRIIB and ActRIIA and has at least one characteristic selected from the group consisting of: (a) competing with an ActRII ligand (e.g., activin A, activin B, GDF1, GDF3, GDF8 (myostatin), GDF11, BMP6, BMP7, BMP9, or BMP10) for binding to ActRIIB and / or ActRIIA; (b) competing with an ActRII ligand (e.g., activin A, activin B, GDF1, GDF3, GDF8 (myostatin), GDF11, BMP6, BMP7, BMP9, or BMP10) for binding to ActRIIB and / or ActRIIA; (c) reduces phosphorylation of Smads (e.g., Smad2 and / or Smad3) in cells expressing ActRIIB and / or ActRIIA, and ALK4 and / or ALK7 in the presence of an ActRIIB and / or ActRIIA ligand (e.g., activin A and / or GDF8 (myostatin)); and (d) a K of ≦1 nM and ≧1 pM. D (e.g., as determined by BIACORE® analysis) binds to ActRIIB. In some embodiments, the ActRIIB and ActRIIA binding protein has two, three, or four of the above characteristics. In some embodiments, the ActRIIB and ActRIIA binding protein has at least two or at least three of the above characteristics. In a further embodiment, the ActRIIB binding protein competes for binding to ActRIIB and ActRIIA with an antibody having an ActRIIB and ActRIIA-binding VH and VL pair disclosed herein. In a further embodiment, the ActRIIB and ActRIIA binding protein is an anti-ActRIIB and ActRIIB antibody or an ActRIIB and ActRIIB-binding antibody fragment.

[0009] In some embodiments, the ActRII binding protein specifically binds to ActRIIA. In a further aspect, the provided ActRII binding proteins specifically bind to ActRIIA and have at least one characteristic selected from the group consisting of: (a) compete with an ActRII ligand (e.g., activin A, activin B, GDF1, GDF3, GDF8 (myostatin), GDF11, BMP6, BMP7, BMP9, or BMP10) for binding to ActRIIA; (b) reduce phosphorylation of ALK4 and / or ALK7 in cells expressing ActRIIA and ALK4 and / or ALK7 in the presence of an ActRIIA ligand (e.g., activin A and / or GDF8 (myostatin)); (c) reduce phosphorylation of Smads (e.g., Smad2 and / or Smad3) in cells expressing ActRIIA in the presence of an ActRIIA ligand (e.g., activin A and / or GDF8); and (d) a K of ≦1 nM and ≧1 pM. D (e.g., as determined by BIACORE® analysis) binds to ActRIIA. In some embodiments, the ActRIIA binding protein has two, three, or four of the above characteristics. In some embodiments, the ActRIIA binding protein has at least two or at least three of the above characteristics. In a further embodiment, the ActRIIA binding protein competes for binding to ActRIIA with an antibody having an ActRIIA-binding VH and VL pair disclosed herein. In a further embodiment, the ActRIIA binding protein is an anti-ActRIIA antibody or an ActRIIA-binding antibody fragment.

[0010] In some embodiments, the ActRII binding protein comprises a set of complementarity determining regions (CDRs): heavy chain variable region (VH)-CDR1, VH-CDR2, VH-CDR3, light chain variable region (VL)-CDR1, VL-CDR2, and VL-CDR3, wherein the CDRs are present in the heavy chain variable region (VH) and light chain variable region (VL) pairs disclosed in Table 1. In some aspects, the ActRII binding protein comprises a set of CDRs present in a VH and VL pair selected from the group consisting of: (a) a VH sequence of SEQ ID NO: 2, 16, 22, 28, 34, or 40 and a VL sequence of SEQ ID NO: 9, the protein binds to ActRIIB; (b) a VH sequence of SEQ ID NO: 63 or 77 and a VL having the amino acid sequence of SEQ ID NO: 70, the protein binds to ActRIIB; (c) a VH sequence of SEQ ID NO: 45 or 57 and a VL sequence of SEQ ID NO: 50, the protein binds to ActRIIB; (d) a VH sequence of SEQ ID NO: 84, 98, 105, 112, or 119 and a VL sequence of SEQ ID NO: 91, the protein binds to ActRIIB and activin receptor type IIA (ActRIIA); and (e) a VH sequence of SEQ ID NO: 125 and a VL sequence of SEQ ID NO: 132, the protein binds to ActRIIA.

[0011] In some aspects, the ActRII binding protein comprises a set of CDRs present in a VH having the amino acid sequence of SEQ ID NO: 144 and a VL having the amino acid sequence of SEQ ID NO: 151, and the protein binds to ActRIIB.

[0012] In some aspects, the ActRII binding protein comprises a set of CDRs present in a VH having the amino acid sequence of SEQ ID NO: 165 and a VL having the amino acid sequence of SEQ ID NO: 172, and the protein binds to ActRIIA and ActRIIB.

[0013] In a further aspect, the ActRII binding protein specifically binds to ActRII and comprises a set of CDRs: VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2, and VL-CDR3, wherein the set of CDRs is identical to the reference set of CDRs or has a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or fewer than 10 amino acid substitutions, deletions, and / or insertions from the reference set of CDRs. The reference set of CDRs includes (a) (i) VH-CDR1 having the amino acid sequence of SEQ ID NO: 3, 17, 23, 29, 35, or 41; (ii) VH-CDR2 having the amino acid sequence of SEQ ID NO: 4, 18, 24, 30, or 36; (iii) VH-CDR3 having the amino acid sequence of SEQ ID NO: 5; (iv) VL-CDR1 having the amino acid sequence of SEQ ID NO: 10; and (v) VL-CDR2 having the amino acid sequence of SEQ ID NO: 11. and (vi) VL-CDR3 has the amino acid sequence of SEQ ID NO: 12; the protein binds to ActRIIB; (b) (i) VH-CDR1 has the amino acid sequence of SEQ ID NO: 64 or 78; (ii) VH-CDR2 has the amino acid sequence of SEQ ID NO: 65 or 79; (iii) VH-CDR3 has the amino acid sequence of SEQ ID NO: 66 or 80; (iv) VL-CDR1 has the amino acid sequence of SEQ ID NO: 71; (i) VH-CDR1 has the amino acid sequence of SEQ ID NO: 3 or 58; (ii) VH-CDR2 has the amino acid sequence of SEQ ID NO: 4 or 59; (iii) VH-CDR3 has the amino acid sequence of SEQ ID NO: 46; (iv) VL-CDR1 is (v) VL-CDR2 has the amino acid sequence of SEQ ID NO: 52; and (vi) VL-CDR3 has the amino acid sequence of SEQ ID NO: 53; the protein binds to ActRIIB; (d) (i) VH-CDR1 has the amino acid sequence of SEQ ID NO: 85, 99, 106, or 113; (ii) VH-CDR2 has the amino acid sequence of SEQ ID NO: 86, 100, 107, 114, or 120;(iii) VH-CDR3 has the amino acid sequence of SEQ ID NO: 87, 101, 108, 115, or 121; (iv) VL-CDR1 has the amino acid sequence of SEQ ID NO: 92; (v) VL-CDR2 has the amino acid sequence of SEQ ID NO: 93; and (vi) VL-CDR3 has the amino acid sequence of SEQ ID NO: 94; the protein binds to ActRIIB and ActRIIA; or (e) (i) VH-CDR1 has the amino acid sequence of SEQ ID NO: 126; (ii) VH-CDR2 has the amino acid sequence of SEQ ID NO: 127; (iii) VH-CDR3 has the amino acid sequence of SEQ ID NO: 128; (iv) VL-CDR1 has the amino acid sequence of SEQ ID NO: 133; (v) VL-CDR2 has the amino acid sequence of SEQ ID NO: 134; and (vi) VL-CDR3 has the amino acid sequence of SEQ ID NO: 135; the protein binds to ActRIIA. ;

[0014] In a further aspect, the ActRII binding protein specifically binds to ActRIIB and comprises a CDR set: VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2, and VL-CDR3, wherein the CDR set is identical to the reference set of CDRs or has a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or fewer than 10 amino acid substitutions, deletions, and / or insertions from the reference set of CDRs. The reference set of CDRs has (i) VH-CDR1 having the amino acid sequence of SEQ ID NO: 145; (ii) VH-CDR2 having the amino acid sequence of SEQ ID NO: 146; (iii) VH-CDR3 having the amino acid sequence of SEQ ID NO: 147; (iv) VL-CDR1 having the amino acid sequence of SEQ ID NO: 152; (v) VL-CDR2 having the amino acid sequence of SEQ ID NO: 153; and (vi) VL-CDR3 having the amino acid sequence of SEQ ID NO: 154.

[0015] In a further aspect, the ActRII binding protein specifically binds to ActRIIA and ActRIIB and comprises a CDR set: VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2, and VL-CDR3, wherein the CDR set is identical to the reference set of CDRs or has a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or less than 10 amino acid substitutions, deletions, and / or insertions from the reference set of CDRs. The reference set of CDRs is as follows: (i) VH-CDR1 has the amino acid sequence of SEQ ID NO: 166; (ii) VH-CDR2 has the amino acid sequence of SEQ ID NO: 167; (iii) VH-CDR3 has the amino acid sequence of SEQ ID NO: 168; (iv) VL-CDR1 has the amino acid sequence of SEQ ID NO: 173; (v) VL-CDR2 has the amino acid sequence of SEQ ID NO: 174; and (vi) VL-CDR3 has the amino acid sequence of SEQ ID NO: 175.

[0016] In some aspects, the ActRII binding protein specifically binds to ActRII and comprises (a) (i) VH-CDR1 having the amino acid sequence of SEQ ID NO: 3, 17, 23, 29, 35, or 41; (ii) VH-CDR2 having the amino acid sequence of SEQ ID NO: 4, 18, 24, 30, or 36; (iii) VH-CDR3 having the amino acid sequence of SEQ ID NO: 5; (iv) VL-CDR1 having the amino acid sequence of SEQ ID NO: 10; (v) VL-CDR2 having the amino acid sequence of SEQ ID NO: 11; and (vi) VL-CDR3 having the amino acid sequence of SEQ ID NO: (i) VH-CDR1 has the amino acid sequence of SEQ ID NO: 64 or 78; (ii) VH-CDR2 has the amino acid sequence of SEQ ID NO: 65 or 79; (iii) VH-CDR3 has the amino acid sequence of SEQ ID NO: 66 or 80; (iv) VL-CDR1 has the amino acid sequence of SEQ ID NO: 71; (v) VL-CDR2 has the amino acid sequence of SEQ ID NO: 72; and (vi) VL-CDR3 has the amino acid sequence of SEQ ID NO: 73; (c) (i) VH-CDR1 has the amino acid sequence of SEQ ID NO: 3 or 58; (ii) VH-CDR2 has the amino acid sequence of SEQ ID NO: 4 or 59; (iii) VH-CDR3 has the amino acid sequence of SEQ ID NO: 46; (iv) VL-CDR1 has the amino acid sequence of SEQ ID NO: 51; (v) VL-CDR2 has the amino acid sequence of SEQ ID NO: 52; and (vi) VL-CDR3 has the amino acid sequence of SEQ ID NO: 53; the protein binds to ActRIIB; (d) (i) VH-CDR1 has the amino acid sequence of SEQ ID NO: 85, (ii) VH-CDR2 has the amino acid sequence of SEQ ID NO: 86, 100, 107, 114, or 120; (iii) VH-CDR3 has the amino acid sequence of SEQ ID NO: 87, 101, 108, 115, or 121; (iv) VL-CDR1 has the amino acid sequence of SEQ ID NO: 92; (v) VL-CDR2 has the amino acid sequence of SEQ ID NO: 93; and (vi) VL-CDR3 has the amino acid sequence of SEQ ID NO: 94; the protein binds to ActRIIB and ActRIIA;or (e) (i) VH-CDR1 has the amino acid sequence of SEQ ID NO: 126; (ii) VH-CDR2 has the amino acid sequence of SEQ ID NO: 127; (iii) VH-CDR3 has the amino acid sequence of SEQ ID NO: 128; (iv) VL-CDR1 has the amino acid sequence of SEQ ID NO: 133; (v) VL-CDR2 has the amino acid sequence of SEQ ID NO: 134; and (vi) VL-CDR3 has the amino acid sequence of SEQ ID NO: 135; wherein the protein comprises a CDR set that binds to ActRIIA;

[0017] In some aspects, the ActRII binding protein specifically binds to ActRIIB and comprises a CDR set in which (i) VH-CDR1 has the amino acid sequence of SEQ ID NO: 145; (ii) VH-CDR2 has the amino acid sequence of SEQ ID NO: 146; (iii) VH-CDR3 has the amino acid sequence of SEQ ID NO: 147; (iv) VL-CDR1 has the amino acid sequence of SEQ ID NO: 152; (v) VL-CDR2 has the amino acid sequence of SEQ ID NO: 153; and (vi) VL-CDR3 has the amino acid sequence of SEQ ID NO: 154.

[0018] In some aspects, the ActRII binding protein specifically binds to ActRIIA and ActRIIB and comprises a CDR set in which (i) VH-CDR1 has the amino acid sequence of SEQ ID NO: 166; (ii) VH-CDR2 has the amino acid sequence of SEQ ID NO: 167; (iii) VH-CDR3 has the amino acid sequence of SEQ ID NO: 168; (iv) VL-CDR1 has the amino acid sequence of SEQ ID NO: 173; (v) VL-CDR2 has the amino acid sequence of SEQ ID NO: 174; and (vi) VL-CDR3 has the amino acid sequence of SEQ ID NO: 175.

[0019] In some aspects, an ActRII binding protein specifically binds ActRII and comprises a set of CDRs having a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, less than 10, or 0 amino acid substitutions, deletions, and / or insertions from a reference set of CDRs. The CDR set comprises: (a)(i) VH-CDR1 has the amino acid sequence of SEQ ID NO: 3; (ii) VH-CDR2 has the amino acid sequence of SEQ ID NO: 4; (iii) VH-CDR3 has the amino acid sequence of SEQ ID NO: 5; (iv) VL-CDR1 has the amino acid sequence of SEQ ID NO: 10; (v) VL-CDR2 has the amino acid sequence of SEQ ID NO: 11; and (vi) VL-CDR3 has the amino acid sequence of SEQ ID NO: 12; wherein the protein binds ActRIIB; and (b)(i) VH-CDR1 has the amino acid sequence of SEQ ID NO: 3; (ii) VH-CDR2 has the amino acid sequence of SEQ ID NO: 4; (iii) VH-CDR3 has the amino acid sequence of SEQ ID NO: 5; (iv) VL-CDR1 has the amino acid sequence of SEQ ID NO: 10; (v) VL-CDR2 has the amino acid sequence of SEQ ID NO: 11; and (vi) VL-CDR3 has the amino acid sequence of SEQ ID NO: 12. (ii) VH-CDR2 has the amino acid sequence of SEQ ID NO: 18; (iii) VH-CDR3 has the amino acid sequence of SEQ ID NO: 5; (iv) VL-CDR1 has the amino acid sequence of SEQ ID NO: 10; (v) VL-CDR2 has the amino acid sequence of SEQ ID NO: 11; and (vi) VL-CDR3 has the amino acid sequence of SEQ ID NO: 12; the protein binds to ActRIIB; (c)(i) VH-CDR1 has the amino acid sequence of SEQ ID NO: 23 (ii) VH-CDR2 has the amino acid sequence of SEQ ID NO: 24; (iii) VH-CDR3 has the amino acid sequence of SEQ ID NO: 5; (iv) VL-CDR1 has the amino acid sequence of SEQ ID NO: 10; (v) VL-CDR2 has the amino acid sequence of SEQ ID NO: 11; and (vi) VL-CDR3 has the amino acid sequence of SEQ ID NO: 12; the protein binds to ActRIIB; (d)(i) VH-CDR1 has the amino acid sequence of SEQ ID NO: 29; (ii) VH-CDR2 is (iii) VH-CDR3 has the amino acid sequence of SEQ ID NO: 5; (iv) VL-CDR1 has the amino acid sequence of SEQ ID NO: 10; (v) VL-CDR2 has the amino acid sequence of SEQ ID NO: 11; and (vi) VL-CDR3 has the amino acid sequence of SEQ ID NO: 12; the protein binds to ActRIIB; (e)(i) VH-CDR1 has the amino acid sequence of SEQ ID NO: 35; (ii) VH-CDR2 has the amino acid sequence of SEQ ID NO: 36;(iii) VH-CDR3 has the amino acid sequence of SEQ ID NO: 5; (iv) VL-CDR1 has the amino acid sequence of SEQ ID NO: 10; (v) VL-CDR2 has the amino acid sequence of SEQ ID NO: 11; and (vi) VL-CDR3 has the amino acid sequence of SEQ ID NO: 12; the protein binds to ActRIIB; (f)(i) VH-CDR1 has the amino acid sequence of SEQ ID NO: 41; (ii) VH-CDR2 has the amino acid sequence of SEQ ID NO: 18; (iii) VH-CDR3 has the amino acid sequence of SEQ ID NO: 5; (iv) VL-CDR1 has the sequence (v) VL-CDR2 has the amino acid sequence of SEQ ID NO: 11; and (vi) VL-CDR3 has the amino acid sequence of SEQ ID NO: 12; the protein binds to ActRIIB; (g) (i) VH-CDR1 has the amino acid sequence of SEQ ID NO: 64; (ii) VH-CDR2 has the amino acid sequence of SEQ ID NO: 65; (iii) VH-CDR3 has the amino acid sequence of SEQ ID NO: 66 or 80; (iv) VL-CDR1 has the amino acid sequence of SEQ ID NO: 71; and (v) VL-CDR2 has the amino acid sequence of SEQ ID NO: 72. and (vi) VL-CDR3 has the amino acid sequence of SEQ ID NO: 73; the protein binds to ActRIIB; and (h) (i) VH-CDR1 has the amino acid sequence of SEQ ID NO: 78; (ii) VH-CDR2 has the amino acid sequence of SEQ ID NO: 79; (iii) VH-CDR3 has the amino acid sequence of SEQ ID NO: 80; (iv) VL-CDR1 has the amino acid sequence of SEQ ID NO: 71; (v) VL-CDR2 has the amino acid sequence of SEQ ID NO: 72; ... binds to ActRIIB; (i)(i) VH-CDR1 has the amino acid sequence of SEQ ID NO: 3; (ii) VH-CDR2 has the amino acid sequence of SEQ ID NO: 4; (iii) VH-CDR3 has the amino acid sequence of SEQ ID NO: 46; (iv) VL-CDR1 has the amino acid sequence of SEQ ID NO: 51; (v) VL-CDR2 has the amino acid sequence of SEQ ID NO: 52; and (vi) VL-CDR3 has the amino acid sequence of SEQ ID NO: 53; the protein binds to ActRIIB; (j)(i) VH-CDR1 has the amino acid sequence of SEQ ID NO: 58;(ii) VH-CDR2 has the amino acid sequence of SEQ ID NO: 59; (iii) VH-CDR3 has the amino acid sequence of SEQ ID NO: 46; (iv) VL-CDR1 has the amino acid sequence of SEQ ID NO: 51; (v) VL-CDR2 has the amino acid sequence of SEQ ID NO: 52; and (vi) VL-CDR3 has the amino acid sequence of SEQ ID NO: 53; the protein binds to ActRIIB; (k)(i) VH-CDR1 has the amino acid sequence of SEQ ID NO: 85; (ii) VH-CDR2 has the amino acid sequence of SEQ ID NO: 86; and (iii) VH-CDR3 has the amino acid sequence (iv) VL-CDR1 has the amino acid sequence of SEQ ID NO: 92; (v) VL-CDR2 has the amino acid sequence of SEQ ID NO: 93; and (vi) VL-CDR3 has the amino acid sequence of SEQ ID NO: 94; the protein binds to ActRIIB and ActRIIA; (l)(i) VH-CDR1 has the amino acid sequence of SEQ ID NO: 99; (ii) VH-CDR2 has the amino acid sequence of SEQ ID NO: 100; (iii) VH-CDR3 has the amino acid sequence of SEQ ID NO: 101; (iv) VL-CDR1 has the amino acid sequence of SEQ ID NO: 92; (v) VL-CDR2 has the amino acid sequence of SEQ ID NO: 93; and (vi) VL-CDR3 has the amino acid sequence of SEQ ID NO: 94; the protein binds to ActRIIB and ActRIIA; (m) (i) VH-CDR1 has the amino acid sequence of SEQ ID NO: 106; (ii) VH-CDR2 has the amino acid sequence of SEQ ID NO: 107, and (iii) VH-CDR3 has the amino acid sequence of SEQ ID NO: 108; (iv) VL-CDR1 has the amino acid sequence of SEQ ID NO: 92; and (v) VL-CDR2 has the amino acid sequence of SEQ ID NO: 93. and (vi) VL-CDR3 has the amino acid sequence of SEQ ID NO: 94; the protein binds to ActRIIB and ActRIIA; (n) (i) VH-CDR1 has the amino acid sequence of SEQ ID NO: 113; (ii) VH-CDR2 has the amino acid sequence of SEQ ID NO: 114; (iii) VH-CDR3 has the amino acid sequence of SEQ ID NO: 115; (iv) VL-CDR1 has the amino acid sequence of SEQ ID NO: 92; (v) VL-CDR2 has the amino acid sequence of SEQ ID NO: 93; and (vi) VL-CDR3 has the amino acid sequence of SEQ ID NO: 94;(i) VH-CDR1 has the amino acid sequence of SEQ ID NO: 113; (ii) VH-CDR2 has the amino acid sequence of SEQ ID NO: 120; (iii) VH-CDR3 has the amino acid sequence of SEQ ID NO: 121; (iv) VL-CDR1 has the amino acid sequence of SEQ ID NO: 92; (v) VL-CDR2 has the amino acid sequence of SEQ ID NO: 93; and (vi) VL-CDR3 has the amino acid sequence of SEQ ID NO: 94; B and ActRIIA; or (p) (i) VH-CDR1 has the amino acid sequence of SEQ ID NO: 126; (ii) VH-CDR2 has the amino acid sequence of SEQ ID NO: 127; (iii) VH-CDR3 has the amino acid sequence of SEQ ID NO: 128; (iv) VL-CDR1 has the amino acid sequence of SEQ ID NO: 133; (v) VL-CDR2 has the amino acid sequence of SEQ ID NO: 134; and (vi) VL-CDR3 has the amino acid sequence of SEQ ID NO: 135; the protein binds to ActRIIA;

[0020] In some aspects, the ActRII binding protein specifically binds to ActRIIB and comprises a CDR set having a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, less than 10, or 0 amino acid substitutions, deletions, and / or insertions from a reference set of CDRs, wherein the reference set of CDRs includes: (i) VH-CDR1 having the amino acid sequence of SEQ ID NO: 145; (ii) VH-CDR2 having the amino acid sequence of SEQ ID NO: 146; (iii) VH-CDR3 having the amino acid sequence of SEQ ID NO: 147; (iv) VL-CDR1 having the amino acid sequence of SEQ ID NO: 152; (v) VL-CDR2 having the amino acid sequence of SEQ ID NO: 153; and (vi) VL-CDR3 having the amino acid sequence of SEQ ID NO: 154.

[0021] In some aspects, the ActRII binding protein specifically binds to ActIIRA and ActRIIB and comprises a CDR set having a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, less than 10, or 0 amino acid substitutions, deletions, and / or insertions from a reference set of CDRs, wherein the reference set of CDRs includes: (i) VH-CDR1 having the amino acid sequence of SEQ ID NO: 166; (ii) VH-CDR2 having the amino acid sequence of SEQ ID NO: 167; (iii) VH-CDR3 having the amino acid sequence of SEQ ID NO: 168; (iv) VL-CDR1 having the amino acid sequence of SEQ ID NO: 173; (v) VL-CDR2 having the amino acid sequence of SEQ ID NO: 174; and (vi) VL-CDR3 having the amino acid sequence of SEQ ID NO: 175.

[0022] In some embodiments, the ActRII binding protein specifically binds ActRII and comprises a VH and VL pair selected from the group consisting of: (a) (i) a VH having at least 90%, 95%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 2, 16, 22, 28, 34, or 40, and (ii) a VL having at least 90%, 95%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 9, wherein the protein binds ActRIIB; (b) (i) a VH having at least 90%, 95%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 45 or 57, and (ii) a VL having at least 90%, 95%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 50, wherein the protein binds ActRIIB; (c) (i) a VH having at least 90%, 95%, 97%, 98%, or 99% sequence identity to SEQ ID NO: (d) (i) a VH having an amino acid sequence of SEQ ID NO: 84, 98, 105, 112, or 119, and (ii) a VL having an amino acid sequence of SEQ ID NO: 91, the protein binds to ActRIIB and ActRIIA; and (e) (i) a VH having at least 90%, 95%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 125, and (ii) a VL having at least 90%, 95%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 132, the protein binds to ActRIIA.

[0023] In some embodiments, the ActRII binding protein specifically binds to ActRIIB and comprises a VH having at least 90%, 95%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 144, and a VL having at least 90%, 95%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 151.

[0024] In some aspects, the ActRII binding protein specifically binds to ActIIRA and ActRIIB and comprises a VH having at least 90%, 95%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 165 and a VL having at least 90%, 95%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 172.

[0025] In a further aspect, the ActRII binding protein comprises a VH and VL pair selected from the group consisting of: (a) a VH sequence of SEQ ID NO: 2, 16, 22, 28, 34, or 40 and a VL sequence of SEQ ID NO: 9; the protein binds to ActRIIB; (b) a VH sequence of SEQ ID NO: 45 or 57 and a VL sequence of SEQ ID NO: 50; the protein binds to ActRIIB; (c) a VH sequence of SEQ ID NO: 63 or 77 and a VL sequence of SEQ ID NO: 70; the protein binds to ActRIIB; (d) a VH sequence of SEQ ID NO: 84, 98, 105, 112, or 119 and a VL sequence of SEQ ID NO: 91; the protein binds to ActRIIB and ActRIIA; and (e) a VH sequence of SEQ ID NO: 125 and a VL sequence of SEQ ID NO: 132; the protein binds to ActRIIA.

[0026] In further aspects, the ActRII binding protein competes for binding to ActRII with an antibody comprising a VH and VL sequence pair disclosed herein. In some aspects, the ActRII binding protein binds to the same epitope as an ActRII binding protein disclosed herein.

[0027] In some aspects, the ActRII binding protein binds to a polypeptide selected from the group consisting of: (a) amino acid residue NANWELERT (SEQ ID NO: 157) of ActRIIB; (b) amino acid residue CCEGNFCNER (SEQ ID NO: 159) of ActRIIB; (c) amino acid residue CCEGNMCNEK (SEQ ID NO: 161) of ActRIIA; and (d) amino acid residue ECLFFNANWEKD (SEQ ID NO: 162) of ActRIIA.

[0028] In a further aspect, the ActRII binding protein comprises the VH sequence of SEQ ID NO: 144 and the VL sequence of SEQ ID NO: 151; and the protein binds to ActRIIB.

[0029] In a further aspect, the ActRII binding protein comprises the VH sequence of SEQ ID NO: 165 and the VL sequence of SEQ ID NO: 172; the protein binds to ActIIRA and ActRIIB.

[0030] In a further aspect, the ActRII binding protein comprises (a) the VH sequence of SEQ ID NO: 2 and the VL sequence of SEQ ID NO: 9; (b) the VH sequence of SEQ ID NO: 16 and the VL sequence of SEQ ID NO: 9; (c) the VH sequence of SEQ ID NO: 22 and the VL sequence of SEQ ID NO: 9; (d) the VH sequence of SEQ ID NO: 28 and the VL sequence of SEQ ID NO: 9; (e) the VH sequence of SEQ ID NO: 34 and the VL sequence of SEQ ID NO: 9; (f) the VH sequence of SEQ ID NO: 40 and the VL sequence of SEQ ID NO: 9; (g) the VH sequence of SEQ ID NO: 45 and the VL sequence of SEQ ID NO: 50; (h) the VH sequence of SEQ ID NO: 57 and the VL sequence of SEQ ID NO: 50; (i) the VH sequence of SEQ ID NO: 16 and the VL sequence of SEQ ID NO: 16; (j) the VH sequence of SEQ ID NO: 77 and the VL sequence of SEQ ID NO: 70; (k) the VH sequence of SEQ ID NO: 84 and the VL sequence of SEQ ID NO: 91; (l) the VH sequence of SEQ ID NO: 98 and the VL sequence of SEQ ID NO: 91; (m) the VH sequence of SEQ ID NO: 105 and the VL sequence of SEQ ID NO: 91; (n) the VH sequence of SEQ ID NO: 112 and the VL sequence of SEQ ID NO: 91; (o) the VH sequence of SEQ ID NO: 119 and the VL sequence of SEQ ID NO: 91; and (p) the VH sequence of SEQ ID NO: 125 and the VL sequence of SEQ ID NO: 132. In a further aspect, the ActRII binding protein comprises a VH having the sequence of SEQ ID NO: 144 and a VL having the sequence of SEQ ID NO: 151. In a further aspect, the ActRII binding protein comprises a VH having the sequence of SEQ ID NO: 165 and a VL having the sequence of SEQ ID NO: 172.

[0031] In some embodiments, the ActRII binding protein comprises a VH and VL pair selected from the group consisting of: (a) (i) a VH sequence having a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15 or fewer than 0 amino acid substitutions, deletions, and / or insertions from a reference VH sequence selected from the group consisting of SEQ ID NOs: 2, 16, 22, 28, 34, or 40, and (ii) a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15 or fewer than 0 amino acid substitutions, deletions, and / or insertions from a reference VL sequence of SEQ ID NO: 9, or and (b) (i) a VH sequence having a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15 or less than 0 amino acid substitutions, deletions, and / or insertions from a reference VH sequence of SEQ ID NO: 45 or 57, and (ii) a VL sequence having a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15 or less than 0 amino acid substitutions, deletions, and / or insertions from a reference VL sequence of SEQ ID NO: 50. (c)(i) a VH sequence having a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15 or less than 0 amino acid substitutions, deletions, and / or insertions from a reference VH sequence of SEQ ID NO: 63 or 77, and (ii) a VL sequence having a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15 or less than 0 amino acid substitutions, deletions, and / or insertions from a reference VL sequence of SEQ ID NO: 70, the protein binds to ActRIIB; (d)(i) a VH sequence having a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15 or less than 0 amino acid substitutions, deletions, and / or insertions from a reference VH sequence selected from the group consisting of SEQ ID NOs: 84, 98, 105, 112, or 119, and (ii) a VL sequence having a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15 or less than 0 amino acid substitutions, deletions, and / or insertions from a reference VL sequence of SEQ ID NO: 91, wherein the protein binds to ActRIIB and ActRIIA;(e) (i) a VH sequence having a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15 or less than 0 amino acid substitutions, deletions, and / or insertions from a reference VH sequence of SEQ ID NO: 125, and (ii) a VL sequence having a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15 or less than 0 amino acid substitutions, deletions, and / or insertions from a reference VL sequence of SEQ ID NO: 132, the protein binds to ActRIIA;

[0032] In some aspects, the ActRII binding protein comprises a VH sequence having a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15 or less than 0 amino acid substitutions, deletions, and / or insertions from the reference VH sequence of SEQ ID NO: 144, and a VL sequence having a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15 or less than 0 amino acid substitutions, deletions, and / or insertions from the reference VL sequence of SEQ ID NO: 151, and the protein binds to ActRIIB.

[0033] In some aspects, the ActRII binding protein comprises a VH sequence having a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15 or less than 0 amino acid substitutions, deletions, and / or insertions from the reference VH sequence of SEQ ID NO: 165, and a VL sequence having a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15 or less than 0 amino acid substitutions, deletions, and / or insertions from the reference VL sequence of SEQ ID NO: 172, and the protein binds to ActIIRA and ActRIIB.

[0034] In a further aspect, an ActRII binding protein comprises a VH and VL pair, wherein (a) the VH sequence has a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15 or less, or 0 amino acid substitutions, deletions, and / or insertions from a reference VH sequence of SEQ ID NO: 2; and the VL sequence has a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15 or less, or 0 amino acid substitutions, deletions, and / or insertions from a reference VL sequence of SEQ ID NO: 9; and the protein binds ActRIIB; and (b) the VH sequence has a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15 or less, or 0 amino acid substitutions, deletions, and / or insertions from a reference VH sequence of SEQ ID NO: 16. , 7, 8, 9, 10, 15, or less than 0 amino acid substitutions, deletions, and / or insertions from the reference VL sequence of SEQ ID NO: 9; and the protein binds ActRIIB; (c) the VH sequence has a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, or less than 0 amino acid substitutions, deletions, and / or insertions from the reference VH sequence of SEQ ID NO: 22; and the VL sequence has a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, or less than 0 amino acid substitutions, deletions, and / or insertions from the reference VL sequence of SEQ ID NO: 9. , 5, 6, 7, 8, 9, 10, 15, or less than 0 amino acid substitutions, deletions, and / or insertions from a reference VH sequence of SEQ ID NO: 28; and a VL sequence of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, or less than 0 amino acid substitutions, deletions, and / or insertions from a reference VL sequence of SEQ ID NO: 9; and a protein that binds ActRIIB; (e) a VH sequence (f) the VH sequence has a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15 or less than 0 amino acid substitutions, deletions, and / or insertions from the reference VH sequence of SEQ ID NO: 34; and the VL sequence has a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15 or less than 0 amino acid substitutions, deletions, and / or insertions from the reference VL sequence of SEQ ID NO: 9; and the protein binds ActRIIB; (f) the VH sequence has a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15 or less than 0 amino acid substitutions, deletions, and / or insertions from the reference VH sequence of SEQ ID NO: 40;and the VL sequence has a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15 or less than 0 amino acid substitutions, deletions, and / or insertions from a reference VL sequence of SEQ ID NO: 9; and the protein binds ActRIIB; (g) the sequence has a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15 or less than 0 amino acid substitutions, deletions, and / or insertions from a reference VH sequence of SEQ ID NO: 45; and the VL sequence has a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15 or less than 0 amino acid substitutions, deletions, and / or insertions from a reference VL sequence of SEQ ID NO: 50. and wherein the protein binds ActRIIB; (h) the VH sequence has a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15 or less than 0 amino acid substitutions, deletions, and / or insertions from the reference VH sequence of SEQ ID NO: 57; and the VL sequence has a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15 or less than 0 amino acid substitutions, deletions, and / or insertions from the reference VL sequence of SEQ ID NO: 50; and the protein binds ActRIIB; (i) the VH sequence has a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15 or less than 0 amino acid substitutions, deletions, and / or insertions from the reference VH sequence of SEQ ID NO: 63. and the VL sequence has a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, or 0 amino acid substitutions, deletions, and / or insertions from the reference VL sequence of SEQ ID NO: 70; and the protein binds ActRIIB; (j) the VH sequence has a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, or 0 amino acid substitutions, deletions, and / or insertions from the reference VH sequence of SEQ ID NO: 77; and the VL sequence has a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, or 0 amino acid substitutions, deletions, and / or insertions from the reference VL sequence of SEQ ID NO: 70. , 6, 7, 8, 9, 10, 15, or less than 0 amino acid substitutions, deletions, and / or insertions; and the protein binds ActRIIB; (k) the sequence has a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, or less than 0 amino acid substitutions, deletions, and / or insertions from the reference VH sequence of SEQ ID NO: 84; and the VL sequence has a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, or less than 0 amino acid substitutions, deletions, and / or insertions from the reference VL sequence of SEQ ID NO: 91; and the protein binds ActRIIB and ActRIIA;(l) the VH sequence has a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15 or less, or 0 amino acid substitutions, deletions, and / or insertions from the reference VH sequence of SEQ ID NO: 98; and the VL sequence has a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15 or less, or 0 amino acid substitutions, deletions, and / or insertions from the reference VL sequence of SEQ ID NO: 91; and the protein binds ActRIIB and ActRIIA; (m) the VH sequence has a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15 or less, or 0 amino acid substitutions, deletions, and / or insertions from the reference VH sequence of SEQ ID NO: 105. and the VL sequence has a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, or 0 amino acid substitutions, deletions, and / or insertions from a reference VL sequence of SEQ ID NO: 91; the protein binds ActRIIB and ActRIIA; (n) the VH sequence has a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, or 0 amino acid substitutions, deletions, and / or insertions from a reference VH sequence of SEQ ID NO: 112; and the VL sequence has a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, or 0 amino acid substitutions, deletions, and / or insertions from a reference VH sequence of SEQ ID NO: 112; (o) the VH sequence has a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15 or less than 0 amino acid substitutions, deletions, and / or insertions from the reference VL sequence of SEQ ID NO: 119; and the VL sequence has a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15 or less than 0 amino acid substitutions, deletions, and / or insertions from the reference VL sequence of SEQ ID NO: 91. or (p) the VH sequence has a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15 or less, or 0 amino acid substitutions, deletions, and / or insertions from the reference VH sequence of SEQ ID NO: 125; and the VL sequence has a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15 or less, or 0 amino acid substitutions, deletions, and / or insertions from the reference VL sequence of SEQ ID NO: 132; and the protein binds to ActRIIA;

[0035] In a further aspect, the ActRII binding protein comprises a VH and VL pair, wherein the VH sequence has a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15 or less, or 0 amino acid substitutions, deletions, and / or insertions from the reference VH sequence of SEQ ID NO: 144, and the VL sequence has a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15 or less, or 0 amino acid substitutions, deletions, and / or insertions from the reference VL sequence of SEQ ID NO: 151; and the protein binds to ActRIIB.

[0036] In a further aspect, the ActRII binding protein comprises a VH and VL pair, wherein the VH sequence has a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15 or less, or 0 amino acid substitutions, deletions, and / or insertions from the reference VH sequence of SEQ ID NO: 165, and the VL sequence has a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15 or less, or 0 amino acid substitutions, deletions, and / or insertions from the reference VL sequence of SEQ ID NO: 172; and the protein binds to ActRIIA and ActRIIB.

[0037] In some embodiments, the ActRII binding protein is an antibody that specifically binds to ActRII. In further embodiments, the antibody is a monoclonal antibody, a recombinant antibody, a human antibody, a humanized antibody, a chimeric antibody, a bispecific antibody, or a multispecific antibody. In some embodiments, the ActRII binding protein is an ActRII-binding antibody fragment. In some embodiments, the antibody is an antibody fragment selected from the group consisting of Fab, Fab', F(ab')2, Fv, a diabody, a DART, and a single-chain antibody molecule (e.g., BiTE).

[0038] Nucleic acids and nucleic acid sets encoding ActRII binding proteins are also provided. Vectors and vector sets containing the nucleic acids and nucleic acid sets, as well as host cells transformed with the nucleic acids and vectors, are also provided. In some embodiments, the host cells are hybridomas or mammalian host cells, such as NS0 mouse myeloma cells, PER.C6® human cells, or Chinese hamster ovary (CHO) cells. Mammalian host cells and host cells, including hybridomas, that produce ActRII binding proteins are also provided.

[0039] Methods for producing ActRII binding proteins are also provided. In some embodiments, the methods include culturing a host cell capable of expressing the ActRII binding protein under appropriate conditions to express the protein and, optionally, to isolate the expressed ActRII binding protein. Also provided are ActRII binding proteins prepared and / or isolated using methods disclosed herein or otherwise known in the art.

[0040] Pharmaceutical compositions comprising an ActRII binding protein and a pharmaceutically acceptable carrier are further provided. In some aspects, the present disclosure provides methods for treating and / or ameliorating a condition in a subject associated with elevated ActRII expression or ActRII-mediated signaling. In some aspects, the method reduces ActRII-mediated signaling in a subject. Use of an ActRII binding protein (e.g., an anti-ActRIIB and / or ActRIIA binding antibody) provided herein in the manufacture or preparation of a medicament is also provided. In some embodiments, the medicament is for treating and / or ameliorating a condition in a subject associated with elevated ActRII expression or ActRII-mediated signaling. In a further embodiment, the present disclosure provides use of an ActRII binding protein provided herein in the manufacture of a medicament for treating a disease or condition described herein.

[0041] Conditions that may be treated and / or ameliorated in a subject using the provided methods include, but are not limited to, muscle disorders, e.g., degenerative muscle diseases, muscular dystrophies, muscle atrophy, or muscle wasting disorders; fibrotic conditions (e.g., fibrotic conditions of the liver, lung, blood vessels, and / or eye, e.g., myocardial fibrosis and idiopathic pulmonary fibrosis (IPF)); metabolic diseases (e.g., insulin-resistant type II diabetes, hyperglycemia, and obesity); inflammatory diseases or conditions, autoimmune diseases, cardiovascular diseases (e.g., congestive heart failure and hypertension); ophthalmic diseases, e.g., age-related macular degeneration; pulmonary diseases, musculoskeletal diseases, skeletal system diseases, e.g., osteoporosis; neurological diseases; neuromuscular diseases, degenerative diseases, wound healing; weight loss; and cancer (e.g., carcinoma, myeloma, osteoinductive loss cancer, pituitary cancer, and gastrointestinal cancer).

[0042] In some embodiments, the method of the present disclosure comprises administering to a subject in need thereof a pharmaceutical composition comprising an effective amount of an ActRII binding protein. In some embodiments, the ActRII binding protein is administered alone. In other embodiments, the ActRII binding protein is administered as a combination therapy. In further embodiments, the ActRII binding protein is administered as a combination therapy with a standard of care treatment / therapy.

[0043] Methods of blocking or reducing ActRII activity (e.g., ligand binding and / or signaling) are also provided. In some embodiments, the method comprises contacting a cell expressing ActRII with an ActRII binding protein. Optionally, the method comprises contacting a cell expressing ActRII with an ActRII binding protein in the presence of an ActRII ligand (e.g., activin A). In some embodiments, the method is performed in vivo. In other embodiments, the method is performed in vitro. In some embodiments, the ActRII activity that is blocked or reduced is phosphorylation of ActRI. In further embodiments, the phosphorylated ActRI is ALK4 and / or ALK7. In further embodiments, the ActRII activity that is blocked or reduced is phosphorylation of Smad (e.g., Smad2 and / or Smad3). In some embodiments, the present disclosure provides a method of blocking or reducing ActRII activity in a subject in need thereof, comprising administering to a subject an effective amount of an ActRII binding protein. In some embodiments, there is provided a method for reducing ActRIIA activity in a subject, comprising administering to a subject in need thereof an effective amount of an ActRIIA binding protein. In some embodiments, there is provided a method for reducing ActRIIB activity in a subject in need thereof, comprising administering to a subject in need thereof an effective amount of an ActRIIB binding protein.

[0044] Also provided are methods for blocking or reducing ActRII activity in pathological conditions associated with increased ActRII expression and / or ActRII signaling, or pathological conditions that can be treated and / or ameliorated by reducing or inhibiting the activity of an ActRII ligand. In some cases, the method comprises administering an ActRII binding protein to a subject with increased expression of ActRII or an ActRII ligand. In some embodiments, the pathological condition is a muscle disorder. In further embodiments, the muscle disorder is atrophy or muscular dystrophy. In some embodiments, the pathological condition is a metabolic condition such as obesity or type II diabetes. In some embodiments, the pathological condition is a pulmonary or hepatic fibrotic condition. In further embodiments, the pathological condition is cancer. In further embodiments, the cancer is myelofibrosis, myeloma (e.g., multiple myeloma), pituitary cancer, breast cancer, gastrointestinal cancer, or carcinoma. In further embodiments, the pathological condition is a bone induction loss cancer (e.g., prostate and breast cancer). In some aspects, the disclosure provides methods of blocking or reducing ActRII activity in pathological conditions associated with cancer therapy-induced bone loss.

[0045] In some aspects, the present disclosure provides methods for treating and / or ameliorating a muscle disorder. In some cases, the method includes administering an ActRII binding protein (e.g., an anti-ActRII antibody) to a subject with a muscle disorder. Further provided is the use of an ActRII binding protein provided herein in the manufacture of a medicament for treating or ameliorating a muscle disorder. In a further aspect, the muscle disorder is atrophy or muscular dystrophy. In other aspects, the subject is at risk of developing a muscle disorder. In a further aspect, the subject is at risk of developing atrophy or muscular dystrophy.

[0046] In some aspects, the present disclosure provides methods for treating and / or ameliorating a fibrotic condition. In some cases, the method includes administering an ActRII binding protein (e.g., in a pharmaceutical composition described herein) to a subject having a fibrotic condition. In other aspects, the subject is at risk of developing a fibrotic condition. In some aspects, the fibrotic condition is chronic. Further provided is the use of an ActRII binding protein provided herein in the manufacture of a medicament for treating or ameliorating a fibrotic condition.

[0047] In some aspects, the present disclosure provides a method for reducing fibrosis in a subject. In some cases, the method includes administering an ActRII binding protein (e.g., an anti-ActRII antibody, such as a full-length ActRII antibody or an ActRII-binding antibody fragment, and variants and derivatives thereof) to a subject with fibrosis. In some aspects, the fibrosis is liver or lung fibrosis. Further provided is the use of the ActRII binding protein provided herein in the manufacture of a medicament for treating or ameliorating fibrosis.

[0048] In another aspect, the present disclosure provides methods for reducing loss of liver or lung function caused by fibrosis in a subject. In some aspects, the methods include administering an ActRII binding protein (e.g., an anti-ActRII antibody, e.g., a full-length ActRII antibody and an ActRII-binding fragment thereof) to a subject in need thereof. In some aspects, the methods reduce loss of liver function in the subject. In some aspects, the methods reduce loss of lung function in the subject. [Brief explanation of the drawings]

[0049] [Figure 1-1]Figures 1A-1N show kinetic characterization of A01 series antibodies binding to hActRIIB and hActRIIA as determined by BIACORE®-based analysis at 37°C. Monomeric or dimeric hActRIIB or hActRIIA was captured on a chip and then exposed to concentrations of A01 series antibodies. Figures 1A-1D show characterization of antibody A01 (parent) binding to ActRIIB monomer (Figure 1A), ActRIIB dimer (Figure 1B), ActRIIA monomer (Figure 1C), and ActRIIA dimer (Figure 1D). Figures 1E and 1F show characterization of antibody B01 binding to ActRIIB monomer (Figure 1E) and ActRIIB dimer (Figure 1F). Figures 1G-1H show antibody C01 binding to ActRIIB monomer (Figure 1G) and ActRIIB dimer (Figure 1H). Figures 1I-1J show antibody D01 binding to ActRIIB monomer (Figure 1I) and ActRIIB dimer (Figure 1J). Figures 1K-1L show antibody E01 binding to ActRIIB monomer (Figure 1K) and ActRIIB dimer (Figure 1L). Figures 1M-1N show antibody F01 binding to ActRIIB monomer (Figure 1M) and ActRIIB dimer (Figure 1N). [Figure 1-2] Figure 1-2 is a continuation of Figure 1-1. [Figure 2] 1 shows the neutralizing activity of A01 series antibodies in a cell-based reporter gene assay, including assay responses with activin A alone (2 ng / ml) and in combination with 50 ng / ml of A01 series antibodies A01, B01, C01, D01, E01, and F01. [Figure 3]Figures 3A-3F show kinetic characterization of G02 series antibodies binding to hActRIIB and hActRIIA as determined by BIACORE®-based analysis at 37°C. Monomeric or dimeric hActRIIB or hActRIIA was captured on the chip and then exposed to the G01 series. Figures 3A-3D show characterization of antibody G01 binding to ActRIIB monomer (Figure 3A), ActRIIB dimer (Figure 3B), ActRIIA monomer (Figure 3C), and ActRIIA dimer (Figure 3D). Figures 1E and 1F show characterization of antibody H01 binding to ActRIIB monomer (Figure 3E) and ActRIIB dimer (Figure 3F). [Figure 4] 1 shows the neutralizing activity of the G01 parental and H01 optimized antibodies in a cell-based reporter gene assay, including assay responses in the absence of activin A, activin A alone (2 ng / ml), and activin A in combination with 50 ng / ml of the G01 series antibodies G01 or H01. [Figure 5-1]Figures 5A-5P show kinetic characterization of A02 series antibodies binding to hActRIIB and hActRIIA as determined by BIACORE®-based analysis at 37°C. Monomeric or dimeric hActRIIB or hActRIIA was captured on a chip and then exposed to A02 series antibodies. Figures 5A-5D show characterization of antibody A02 (parent) binding to ActRIIB monomer (Figure 5A), ActRIIB dimer (Figure 5B), ActRIIA monomer (Figure 5C), and ActRIIA dimer (Figure 5D). Figures 5E-5H show characterization of antibody B02 binding to ActRIIB monomer (Figure 5E), ActRIIB dimer (Figure 5F), ActRIIA monomer (Figure 5G), and ActRIIA dimer (Figure 5H). Figures 5I-5L show the characterization of antibody C02, which binds to ActRIIB monomer (Figure 5I), ActRIIB dimer (Figure 5J), ActRIIA monomer (Figure 5K), and ActRIIA dimer (Figure 5L). Figures 5M-5P show the characterization of antibody D02, which binds to ActRIIB monomer (Figure 5M), ActRIIB dimer (Figure 5N), ActRIIA monomer (Figure 5O), and ActRIIA dimer (Figure 5P). Figures 5Q-5T show the characterization of antibody D03, which binds to ActRIIB monomer (Figure 5Q), ActRIIB dimer (Figure 5R), ActRIIA monomer (Figure 5S), and ActRIIA dimer (Figure 5T). [Figure 5-2] Figure 5-2 is a continuation of Figure 5-1. [Figure 5-3] Figure 5-3 is a continuation of Figure 5-2. [Figure 6] Figures 6A-6B show the neutralizing activity of A02 series antibodies in a cell-based reporter gene assay. Included are assay responses in the absence of activin A, activin A alone (2 ng / ml), and activin A in combination with 50 ng / ml of A02 series antibodies. Figure 6A shows the neutralizing activity of A02 (parent), B02, C02, and D02. Figure 6B shows the neutralizing activity of D02 and D03. [Figure 7]Figures 7A-7F show kinetic characterization of E02 parent and F02 mutant antibody binding to hActRIIB and hActRIIA as determined by BIACORE®-based analysis at 37°C. Monomeric or dimeric hActRIIB or hActRIIA was captured on the chip and then exposed to E02 and F02. Figures 7A-7D show characterization of E02 parent binding to ActRIIB monomer (Figure 7A), ActRIIB dimer (Figure 7B), ActRIIA monomer (Figure 7C), and ActRIIA dimer (Figure 7D). Figures 7E and 7F show characterization of antibody F02 binding to ActRIIB monomer (Figure 7E) and ActRIIB dimer (Figure 7F). [Figure 8] Figures 8A-8D show kinetic characterization of antibody G02 binding to hActRIIB and hActRIIA as determined by BIACORE®-based analysis at 37°C. Monomeric or dimeric hActRIIB or hActRIIA was captured on the chip and then exposed to the anti-hActRII antibodies evaluated. Figures 8A-8D show characterization of antibody G02 binding to ActRIIB monomer (Figure 8A), ActRIIB dimer (Figure 8B), ActRIIA monomer (Figure 8C), and ActRIIA dimer (Figure 8D). [Figure 9] 1 shows the neutralizing activity of ActRIIB-binding E02 parent and F02 mutant antibodies and ActRIIA-binding antibody G02 in a cell-based reporter gene assay, including assay responses in the absence of activin A, activin A alone (2 ng / ml), and activin A in combination with 50 ng / ml of antibodies E02, F02, or G02. DETAILED DESCRIPTION OF THE INVENTION

[0050] The present disclosure provides isolated recombinant ActRII binding proteins. In certain embodiments, the ActRII binding proteins specifically bind to ActRIIB and / or ActRIIA. In further embodiments, the ActRII binding proteins are anti-ActRII antibodies. Nucleic acids encoding the ActRII binding proteins, vectors and host cells containing the nucleic acids, and methods for making and using the ActRII binding proteins are also provided. The provided ActRII binding proteins are used to diagnose, treat, and / or ameliorate diseases and conditions associated with increased ActRII expression and / or signaling. Such uses include, but are not limited to, preventing and / or ameliorating muscle disorders, such as degenerative muscle diseases, muscular dystrophies, muscle atrophy or muscle wasting disorders; fibrotic conditions (e.g., fibrotic conditions of the liver, lung, blood vessels and / or eye, such as myocardial fibrosis and idiopathic pulmonary fibrosis (IPF)); metabolic diseases (e.g., type II diabetes and obesity); inflammatory diseases or conditions, autoimmune diseases, cardiovascular diseases (e.g., congestive heart failure and hypertension); ophthalmic diseases, such as age-related macular degeneration; pulmonary diseases, musculoskeletal diseases, skeletal diseases, neurological diseases, such as osteoporosis; wound healing; weight loss; and cancer (e.g., carcinoma, myeloma, osteoinductive loss cancer, pituitary cancer, and gastrointestinal cancer).

[0051] definition Unless otherwise defined, all scientific and technical terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains. For example, Concise Dictionary of Biomedicine and Molecular Biology, Juo, Pei-Show, 2nd ed., 2002, CRC Press; The Dictionary of Cell and Molecular Biology, 3rd ed., 1999, Academic Press; and Oxford Dictionary of Biochemistry and Molecular Biology, Revised, 2000, Oxford University Press provide those skilled in the art with a general dictionary of many of the terms used in this disclosure. The headings provided herein are not limitations of the various aspects that may be had by reference to the specification as a whole. Accordingly, the terms defined immediately below are more fully defined by reference to the specification as a whole.

[0052] The terms "a," "an," and "the" include plural referents unless the context in which they are used clearly dictates otherwise. The terms "a" (or "an") and "one or more" and "at least one" can be used interchangeably herein. Furthermore, "and / or," when used herein, should be construed as a specific disclosure of two or more specified features or components, each with or without the other. Thus, the term "and / or," when used herein in phrases such as "A and / or B," is intended to include "A and B," "A or B," "A" (alone), and "B" (alone). Similarly, the term "and / or," when used in phrases such as "A, B, and / or C," is intended to encompass each of the following embodiments: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone).

[0053] The term "comprise" is used generally to mean including allowing for the presence of one or more features or components. Whenever an embodiment is described herein using the language "comprising," other similar embodiments described with the terms "consisting of" and / or "consisting essentially of" are also provided.

[0054] The terms "about" and "approximately" used in connection with numerical values ​​throughout this specification and claims indicate an accuracy within a certain range that is familiar and acceptable to those skilled in the art. Generally, such accuracy within a certain range is ±10%. Alternatively, and particularly in biological systems, the terms "about" and "approximately" can mean values ​​within an order of magnitude of a given value, preferably ≦5-fold, and more preferably ≦2-fold.

[0055] Numeric ranges are inclusive of the numbers defining the range.

[0056] An ActRII-binding protein refers to a protein that specifically binds to ActRII (i.e., ActRIIB and / or ActRIIA), preferably to the extracellular domain of ActRII.

[0057] The terms "ActRII activin receptor type II" and "ActRII" are used interchangeably and refer to activin receptor type IIA (ActRIIA) and / or activin receptor type IIB (ActRIIB), unless the context in which the term is used clearly indicates otherwise.

[0058] The terms "activin receptor type IIA," "ActRIIA receptor," and "ActRIIA" are used interchangeably herein to refer to ActRIIA (also referred to in the literature as ACVR2A, ActRIIA, ActRII, and EC 2.7.11.30). A reference sequence for human ActRIIA is provided in reference SEQ ID NO: NP_001607.1. The provided ActRIIA-binding proteins bind to the extracellular domain of ActRIIA corresponding to the amino acid sequence of SEQ ID NO: 138.

[0059] The terms "activin receptor type IIB," "ActRIIB receptor," and "ActRIIB" are used interchangeably and refer to ActRIIB (also referred to in the literature as ACVR2B, ActRIIB, HTX4, ErbB3 receptor, and EC 2.7.11.30). The reference sequence for human ActRIIB is provided in NCBI reference sequence NP_001097. The provided ActRIIB-binding proteins bind to the extracellular domain of ActRIIB corresponding to the amino acid sequence of SEQ ID NO: 139.

[0060] The term "compete" or "competes," when used in the context of an ActRII-binding protein (e.g., a neutralizing antibody), refers to competition between antigen-binding proteins as determined by an assay in which the antigen-binding protein under test (e.g., an anti-ActRII antibody or ActRII-binding fragment thereof) prevents or inhibits specific binding of a reference antigen-binding protein (e.g., a ligand, or reference antibody) to a common antigen (e.g., an ActRIIA or ActRIIB extracellular domain or fragment thereof). Many types of competitive binding assays can be used. For example, solid-phase direct or indirect radioimmunoassays (RIA) (see, e.g., Moldenhauer et al., Scand. J. Immunol. 32:77-82 (1990) and Morel et al., Molec. Immunol. 25:7-15 (1988)), solid-phase direct or indirect enzyme immunoassays (EIA), solid-phase direct biotin-avidin EIA (see, e.g., Cheung et al., Virology 176:546-552 (1990) and Kirkland et al., J. Immunol. 137:3614-3619 (1986)), and sandwich competition assays (see, e.g., Stahl et al., Methods in Enzymology 92:242-253 (1983)). Typically, such assays involve the use of purified antigen bound to a solid surface or cells bearing either of these unlabeled test antigen binding proteins and a labeled reference antigen binding protein.

[0061] Competitive inhibition can be measured by determining the amount of label bound to a solid surface or cells in the presence of a test antigen-binding protein. Typically, the test antigen-binding protein is present in excess. Antigen-binding proteins identified by competitive assays (competing with antigen-binding proteins) include ActRII-binding proteins that bind to the same epitope as the reference ActRII-binding protein, as well as ActRII-binding proteins that bind to adjacent epitopes that are sufficiently close to the epitope bound by the reference ActRII-binding protein to sterically hinder it. Typically, when a competing ActRII (e.g., ActRIIA or ActRIIB)-binding protein is present in excess, it will inhibit the specific binding of the reference ActRII-binding protein ActRII (e.g., ActRIIA or ActRIIB) by at least 40%, 45%, 50%, 55%, 60%, 65%, 70%, or 75%. In some cases, the competing antigen binding protein inhibits specific binding of the reference ActRII binding protein by at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%.

[0062] The term "epitope," when used in the context of an ActRII protein, refers to an ActRII (e.g., human ActRIIA, human ActRIIB, mouse ActRIIA, or mouse ActRIIA) protein determinant that can bind to an ActRII binding protein (e.g., an antibody) of the present disclosure. Epitopes typically consist of chemically active surface groupings of molecules such as amino acids or sugar side chains and typically have specific three-dimensional structural characteristics, as well as specific charge characteristics. Conformational and nonconformational epitopes are distinguished in that the binding to the former but not the latter is lost in the presence of denaturing solvents. The ActRII epitope bound by an ActRII binding protein can be readily determined using techniques known in the art.

[0063] Antigen-binding proteins, such as the anti-ActRII-binding antibodies disclosed herein, and their ActRII-binding fragments, variants, or derivatives, can be described or specified in terms of the epitope(s) or portion(s) of an antigen, e.g., a target polypeptide, that they recognize or specifically bind to. For example, a portion of ActRII that specifically interacts with the antigen-binding domain of an ActRII-binding protein disclosed herein is an "epitope." An "epitope" can be formed from both contiguous amino acids or noncontiguous amino acids juxtaposed by tertiary folding of a protein. Epitopes formed from contiguous amino acids are typically retained by exposure to denaturing solvents, while epitopes formed by tertiary folding are typically lost by treatment with denaturing solvents. Epitopic determinants can include chemically active surface molecular groupings, such as amino acids, sugar side chains, phosphoryl, or sulfonyl groups, and can have specific three-dimensional structural and / or charge characteristics. An epitope typically includes at least 3, 4, 5, 6, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35 amino acids in a unique spatial conformation. Epitopes can be routinely determined using methods known in the art.

[0064] The terms "inhibit," "block," "reduce," "decrease," "suppress," "antagonize," and "neutralize" are used interchangeably and refer to any statistically significant decrease in activity (e.g., ActRII ligand binding and ActRII signaling), including complete blockage of activity. For example, "inhibition" or "suppression" can refer to about a 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% decrease in activity compared to a control.

[0065] In some aspects, the term "reduce" can refer to the ability of an ActRII-binding protein, such as an antibody or ActRII-binding fragment thereof, to statistically significantly (e.g., with a p-value of 0.05 or less) reduce the phosphorylation of one or more Smads (e.g., Smad2 and / or Smad3) induced by contacting cells expressing ActRII and type I receptors with an ActRII ligand, such as activin A, compared to the degree of Smad phosphorylation in the cells not contacted with the ActRII-binding protein. Cells expressing ActRII (e.g., ActRIIB and / or ActRIIA) can be naturally occurring cells or cell lines, or can be recombinantly produced by introducing nucleic acid encoding ActRII (e.g., ActRIIB and / or ActRIIA) into a host cell. In one aspect, the ActRII binding protein, e.g., an ActRII antibody or ActRII binding fragment thereof, reduces ActRII ligand-mediated phosphorylation of one or more Smads (e.g., Smad2 and / or Smad3) by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 95%, or about 100%, as determined by Western blotting followed by probing with an anti-phosphotyrosine antibody or by ELISA using standard techniques and conditions described herein or otherwise known in the art.

[0066] In some aspects, the ActRIIA binding protein reduces ActRIIA ligand (e.g., activin A)-mediated phosphorylation of one or more Smads (e.g., Smad2 and / or Smad3) by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 95%, or about 100%, as determined using techniques described herein or otherwise known in the art, e.g., by Western blotting followed by probing with an anti-phosphotyrosine antibody, or by ELISA (e.g., P-Smad ELISA) or Smad-dependent reporter gene assay.

[0067] In a further aspect, the ActRIIB binding protein reduces ActRIIB ligand (e.g., activin A or GDF8)-mediated phosphorylation of one or more Smads (e.g., Smad2 and / or Smad3) by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 95%, or about 100%, as determined using standard techniques and conditions described herein or known in the art, for example, by Western blotting followed by probing with an anti-phosphotyrosine antibody, or by ELISA (e.g., P-Smad ELISA) or Smad-dependent reporter gene assay.

[0068] The terms "antibody" or "immunoglobulin" are used interchangeably herein and include whole (full-length) antibodies and antigen-binding fragments or single chains thereof. A typical antibody comprises at least two heavy (H) chains and two light (L) chains interconnected by disulfide bonds. Each heavy chain comprises a heavy chain variable region (abbreviated herein as VH) and a heavy chain constant region. The heavy chain constant region comprises three domains, CH1, CH2, and CH3. Each light chain comprises a light chain variable region (abbreviated herein as VL) and a light chain constant region. The light chain constant region comprises one domain, CL. The VH and VL regions can be further subdivided into hypervariable regions, called complementarity-determining regions (CDRs), interspersed with more conserved regions, called framework regions (FW). Each VH and VL comprises three CDRs and four FWs arranged from amino-terminus to carboxy-terminus in the following order: FW1, CDR1, FW2, CDR2, FW3, CDR3, FW4. The variable regions of the heavy and light chains contain a binding domain that interacts with an antigen. The constant region of the antibody can mediate the binding of the immunoglobulin to host tissues or factors, including various immune system cells (e.g., effector cells) and the first component (C1q) of the classical complement system. Exemplary antibodies include conventional antibodies, scFvs, and combinations thereof, where, for example, the scFv is covalently linked (e.g., via a peptide bond or chemical linker) to the N- or C-terminus of either the heavy and / or light chain of the conventional antibody, or inserted into the heavy and / or light chain of the conventional antibody.

[0069] The terms "antibody" and "immunoglobulin" encompass intact polyclonal antibodies, intact monoclonal antibodies, antibody fragments (e.g., Fab, Fab', F(ab'), and Fv fragments), single-chain Fv (scFv) derivatives and mutants, multispecific antibodies such as bispecific antibodies, chimeric antibodies, humanized antibodies, human antibodies, fusion proteins containing an antigenic determinant of an antibody, and any other modified immunoglobulin molecule containing an antigen recognition site, so long as the antibody exhibits the desired binding activity. Antibodies can belong to any of the five major immunoglobulin classes: IgA, IgD, IgE, IgG, and IgM, or their subclasses (isotypes) (e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2), based on the identity of their heavy chain constant domains, designated α, δ, ε, γ, and μ, respectively. Different immunoglobulin classes have distinct and well-known subunit structures and three-dimensional configurations. Antibodies can be naked or conjugated to other molecules, such as toxins, radioisotopes, etc. The term "IgG" refers to a polypeptide belonging to the class of antibodies substantially encoded by the recognized immunoglobulin gamma gene. In humans, this class includes IgG1, IgG2, IgG3, and IgG4. In mice, this class includes IgG1, IgG2a, IgG2b, and IgG3.

[0070] The terms "ActRII antibody," "antibody that binds to ActRII," or "anti-ActRII antibody" refer to an antibody that can bind to ActRII (e.g., ActRIIB and / or ActRIIA) with sufficient affinity such that the antibody is useful as a therapeutic or diagnostic reagent targeting ActRIIB and / or ActRIIA, respectively.

[0071] "Specifically binds," when used in the context of ActRII protein, generally refers to the ability of a binding protein, such as an antibody, to bind to ActRII (e.g., ActRIIB and / or ActRIIA, preferably human ActRIIA and / or human ActRIIB, preferably the extracellular domain of ActRIIB and / or ActRIIA) with greater affinity than the binding protein binds to an unrelated control protein. In some embodiments, the control protein is hen egg white lysozyme. Preferably, the binding protein binds to ActRII with an affinity that is at least 100, 500, or 1000 times greater than the affinity for the control protein. Preferably, the binding protein binds to ActRII with an affinity of ≦1×10 as measured by binding assays known in the art. -7 M or ≤ 1 × 10 -8 In some embodiments, the binding affinity is measured using a radioimmunoassay (RIA) or BIACORE® (e.g., ActRII (e.g., ActRIIB and / or ActRIIA) as the analyte and an ActRII-binding protein as the ligand, or vice versa).

[0072] In some embodiments, the extent of binding of an ActRII binding protein (e.g., an anti-ActRII antibody) to an unrelated, non-ActRII protein is less than about 10% of the binding of the ActRII binding protein to ActRII as measured, for example, by radioimmunoassay (RIA), BIACORE® (using recombinant ActRII as the analyte and the ActRII binding protein as the ligand, or vice versa), equilibrium exclusion assay (KINEXA®), or other binding assays known in the art. In certain embodiments, the ActRII binding protein has a dissociation constant (K) of ≦1 μM, ≦100 nM, ≦10 nM, ≦1 nM, ≦0.1 nM, ≦10 pM, ≦1 pM, or ≦0.1 pM. D ) is a full-length antibody or an ActRII-binding antibody fragment.

[0073] The terms "antigen-binding antibody fragment" (e.g., "ActRII-binding antibody fragment," "ActRIIA-binding antibody fragment," and "ActRIIB-binding antibody fragment") refer to a fragment containing all or part of the antigen-binding variable region (e.g., CDR3) of an intact antibody. It is known that the antigen-binding function of an antibody can be performed by fragments of a full-length antibody. Examples of antibody fragments include, but are not limited to, Fab, Fab', F(ab')2, and Fv fragments, linear antibodies, single-chain antibodies, and multispecific antibodies formed with one or more antibody fragments. In some aspects, the present disclosure provides an ActRII-binding antibody fragment, wherein the antibody fragment is a Fab fragment, a Fab' fragment, a F(ab')2 fragment, an Fv fragment, a diabody, or a single-chain antibody molecule.

[0074] The Fc region includes the polypeptides comprising the constant region of an antibody excluding the first constant region immunoglobulin domain. Thus, Fc refers to the last two constant region immunoglobulin domains of IgA, IgD, and IgG, and the last three constant region immunoglobulin domains of IgE and IgM, as well as the flexible hinge at the N-terminus of these domains. For IgA and IgM, Fc may include the J chain. For IgG, Fc includes immunoglobulin domains Cγ2 and Cγ3 and the hinge between Cγ1 and Cγ2. Although the boundaries of the Fc region can vary, the human IgG heavy chain Fc region is usually defined to include residues C226 or P230 at its carboxyl terminus (where numbering is according to the EU index as defined in Kabat (Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md. (1991))). Fc can refer to this region independently, or in the context of a whole antibody, antibody fragment, or Fc fusion protein. Polymorphisms have been observed at many different Fc positions, including but not limited to positions 270, 272, 312, 315, 356, and 358 as numbered by the EU index; therefore, small differences may exist between the presented sequence and prior art sequences.

[0075] A "monoclonal antibody" refers to a homogeneous antibody population responsible for highly specific recognition and binding of a single antigenic determinant or epitope. This is in contrast to polyclonal antibodies, which typically include different antibodies directed against different antigenic determinants. The term "monoclonal antibody" encompasses both intact and full-length monoclonal antibodies, as well as antibody fragments (Fab, Fab', F(ab')2, Fv, etc.), single-chain (scFv) mutants, and fusion proteins containing an antibody portion and any other modified immunoglobulin molecule containing an antigen recognition site. Monoclonal antibodies can be produced in any number of ways, including, but not limited to, by hybridoma, phage selection, recombinant expression, and transgenic animals.

[0076] The term "chimeric antibody" refers to an antibody in which the amino acid sequences of the immunoglobulin molecule are derived from two or more species. Typically, the variable regions of both the light and heavy chains correspond to the variable regions of antibodies derived from one species of mammal (e.g., mouse, rat, rabbit, etc.) having the desired antigen-binding specificity, affinity, and / or capacity, while the constant regions are homologous to the sequences of antibodies derived from another species (usually human) to avoid eliciting an immune response in that species.

[0077] The term "humanized antibody" refers to an antibody derived from a non-human (e.g., murine) immunoglobulin that has been genetically engineered to contain fewer, preferably minimal, non-human (e.g., murine) sequences. Typically, humanized antibodies are human immunoglobulins in which CDR residues are replaced by residues from the CDRs of a non-human species (e.g., mouse, rat, rabbit, or hamster) having the desired antigen-binding specificity, affinity, and / or capacity (Jones, Nature 321:522-525 (1986); Riechmann, Nature 332:323-327 (1988); Verhoeyen, Science 239:1534-1536 (1988)). In some cases, Fv framework region (FW) residues of the human immunoglobulin are replaced by corresponding residues from an antibody from a non-human species having the desired antigen-binding specificity, affinity, and / or capacity. Humanized antibodies can be further modified by substituting additional residues within the Fv framework regions and / or the replaced non-human residues to refine and optimize the antibody's specificity, affinity, and / or capacity. Generally, a humanized antibody will comprise substantially all of at least one, and typically two or three, variable domains containing all or substantially all of the CDR regions corresponding to a non-human immunoglobulin, while all or substantially all of the FR regions are of human immunoglobulin consensus sequences. A humanized antibody can also comprise at least a portion of an immunoglobulin constant region or domain (Fc), typically that of a human immunoglobulin. Examples of methods used to make humanized antibodies are described in U.S. Patent Nos. 5,225,539 or 5,639,641.

[0078] The term "human antibody" refers to an antibody produced by a human, or an antibody having an amino acid sequence corresponding to an antibody produced by a human, made using any technique known in the art. The term "human antibody" includes intact (full-length) antibodies, fragments thereof, and / or antibodies comprising at least one human heavy and / or light chain polypeptide, such as an antibody comprising a murine light chain and a human heavy chain polypeptide.

[0079] An "antagonist," "blocking," or "neutralizing" binding protein is one that inhibits or reduces the activity of an antigen to which it binds, such as ActRIIB and / or ActRIIA. In some embodiments, an antagonist ActRII binding protein reduces or inhibits binding to ActRIIA by an ActRIIA ligand, such as activin A. In some embodiments, an antagonist ActRII binding protein reduces or inhibits binding to ActRIIB by an ActRIIB ligand, such as activin A. In certain embodiments, an antagonist ActRII binding protein substantially or completely inhibits the activity of ActRII. In some embodiments, ActRII activity is reduced by 10%, 20%, 30%, 50%, 70%, 80%, 90%, 95%, or 100%. In certain embodiments, the antagonist ActRII binding protein is an anti-ActRIIA antibody, e.g., a full-length antibody or an ActRIIA-binding antibody fragment. In further embodiments, the antagonist anti-ActRIIA antibody inhibits or reduces ActRIIA activity by at least 10%, 20%, 30%, 50%, 70%, 80%, 90%, 95%, or 100%. In further embodiments, the antagonist ActRII binding protein is an anti-ActRIIB antibody, e.g., a full-length antibody or an ActRIIB-binding antibody fragment. In further embodiments, the antagonist anti-ActRIIB antibody inhibits or reduces ActRIIB activity by at least 10%, 20%, 30%, 50%, 70%, 80%, 90%, 95%, or 100%.

[0080] "Binding affinity" generally refers to the strength of the sum total of non-covalent interactions between a single binding site of a molecule (e.g., an antibody) and its binding partner (e.g., an antigen). Unless otherwise indicated, "binding affinity" refers to the intrinsic binding affinity, which reflects a 1:1 interaction between members of a binding pair (e.g., an antibody and an antigen). The affinity of a molecule X for its partner Y is generally determined by the dissociation constant (K DAffinity can be measured by common methods known in the art, including those described herein, and can be used for the purposes of this disclosure.

[0081] "Potency" is a measure of a compound's pharmacological activity expressed as the amount of compound required to produce an effect of a given strength. Potency refers to the amount of compound required to achieve a defined biological effect; the lower the dose required, the more potent the drug. Potency is usually expressed as an IC in nM unless otherwise specified. 50 It is expressed as a value. 50 is the median inhibitory concentration of an ActRII-binding protein (e.g., an anti-ActRIIA or anti-ActRIIB antibody). In functional assays, the IC 50 is the concentration that reduces a biological response by 50% of its maximum. In ligand-receptor binding studies, the IC 50 is the concentration that reduces ligand-receptor binding by 50% of the maximal specific binding level. 50 can be calculated by any number of means known in the art. The fold improvement in potency of an antibody or other binding protein provided herein compared to a reference anti-ActRII antibody or other ActRII binding protein can be at least 2-fold, 4-fold, 6-fold, 8-fold, 10-fold, 20-fold, 30-fold, 40-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 110-fold, 120-fold, 130-fold, 140-fold, 150-fold, 160-fold, 170-fold, or at least 180-fold.

[0082] "Antibody-dependent cell-mediated cytotoxicity" or "ADCC" refers to a form of cytotoxicity in which secreted Ig bound to Fc receptors (FcRs) present on certain cytotoxic cells (e.g., natural killer (NK) cells, neutrophils, and macrophages) enables these cytotoxic effector cells to specifically bind to antigen-bearing target cells and subsequently kill the target cells with cytotoxins. Specific high-affinity IgG antibodies directed to the surface of target cells "arm" the cytotoxic cells and are essential for such killing. Lysis of target cells is extracellular, requires direct cell-to-cell contact, and does not involve complement. In addition to antibodies, other proteins containing an Fc region capable of specifically binding to ActRII-bearing target cells, specifically Fc fusion proteins, are believed to be capable of achieving cell-mediated cytotoxicity. For simplicity, cell-mediated cytotoxicity resulting from the activity of Fc fusion proteins is also referred to herein as ADCC activity.

[0083] An "isolated" ActRII-binding protein (e.g., an ActRII antibody (including ActRII-binding fragments, variants, and derivatives thereof)), polynucleotide, vector, cell, or composition is a protein (e.g., an antibody), polynucleotide, vector, cell, or composition that is in a form not found in nature. Isolated proteins, polynucleotides, vectors, cells, or compositions include those that have been purified to the extent that they are no longer in a form found in nature. In some embodiments, an isolated protein, polynucleotide, vector, cell, or composition is substantially pure. Isolated proteins and isolated nucleic acids are free or substantially free from other polypeptides or nucleic acids with which they are naturally associated, e.g., found in their natural environment, or in the environment in which they are prepared (e.g., cell culture), if such preparation is based on recombinant DNA techniques practiced in vitro or in vivo. Proteins and nucleic acids can be formulated with a diluent or adjuvant and still be isolated for practical purposes - for example, proteins will usually be mixed with gelatin or other carrier if used to coat microtiter plates for use in immunoassays, or mixed with a pharmaceutically acceptable carrier or diluent when used diagnostically or therapeutically.

[0084] The terms "subject," "individual," "animal," "patient," and "mammal" refer to any subject, particularly a mammalian subject, for whom diagnosis, prognosis, or treatment is desired. Mammalian subjects include, but are not limited to, humans, non-human primates, domestic animals, farm animals, rodents, etc., and are intended to be the recipient of a particular treatment.

[0085] The term "pharmaceutical composition" refers to a preparation in a form that allows the biological activity of the active ingredient to be effective and that does not contain additional components at concentrations that are unacceptably toxic to the subject to which the composition is to be administered. Such compositions may be sterile.

[0086] An "effective amount" of a polypeptide, e.g., an antigen-binding protein, including an antibody, disclosed herein is an amount sufficient to carry out a specifically described purpose. An "effective amount" can be routinely determined empirically for the described purpose. The term "therapeutically effective amount" refers to an amount of a polypeptide, e.g., an antigen-binding protein, including an antibody, or other drug effective to "treat" a disease or condition in a subject (e.g., a mammal such as a human) and bring about some improvement or benefit to a subject with the disease or condition. Thus, a "therapeutically effective" amount is an amount that brings about some alleviation, mitigation, and / or reduction of at least one clinical symptom of an ActRII-mediated disease or condition. Clinical symptoms associated with diseases or conditions that can be treated by the disclosed methods are well known. Furthermore, the therapeutic effect need not be complete or curative, as long as some benefit is conferred on the subject. In some embodiments, the term "therapeutically effective" refers to an amount of a therapeutic agent capable of reducing ActRII activity in a patient in need thereof. The actual amount administered, as well as the rate and time-course of administration, will depend on the nature and severity of the condition being treated. Prescribing treatment, e.g., determining dosage, is the responsibility of general practitioners and other physicians. Appropriate doses of antibodies and antigen-binding fragments thereof are generally known; see Ledermann et al. Int. J. Cancer 47:659-664 (1991); Bagshawe et al. Ant, Immun. and Radiopharm. 4:915-922 (1991).

[0087] A "sufficient amount" or "an amount sufficient to achieve a particular result in a patient having an ActRII-mediated disease or condition" refers to an amount of a therapeutic agent (e.g., an antigen binding protein, including an antibody, disclosed herein) that is effective to produce a desired effect, which is a therapeutic effect, as needed (i.e., by administration of a therapeutically effective amount). In some embodiments, such a particular result is a decrease in ActRII activity in a patient in need thereof.

[0088] The term "label" refers to a detectable compound or composition that is directly or indirectly conjugated to a moiety, such as an anti-ActRII antibody, thereby producing a "labeled" moiety. The label may itself be detectable (e.g., a radioisotope label or a fluorescent label) or, in the case of an enzymatic label, may catalyze the chemical modification of a substrate compound or composition that is detectable.

[0089] Terms such as "treat" or "treatment" or "treating" or "ameliorate" or "ameliorating" refer to both (a) therapeutic measures that cure, slow, relieve the symptoms, and / or halt the progression of a diagnosed pathological condition or disorder, and (b) preventative or prophylactic measures that prevent and / or delay the onset of the targeted disease or condition. Thus, subjects in need of treatment include those who already have the disease or condition; those at risk of developing the disease or condition; and those in whom the disease or condition is to be prevented. In certain aspects, a subject is successfully "treated" by the methods provided herein if the subject exhibits, for example, complete, partial, or temporary improvement or elimination of symptoms associated with the disease or condition. In some aspects, the present disclosure provides methods of treating muscle disorders, such as muscle wasting due to disease or disuse. In a further aspect, the present disclosure provides a method of treating a disease or condition selected from muscle disorders, e.g., degenerative muscle diseases, muscular dystrophy, muscle atrophy, or muscle wasting disorders; fibrotic conditions (e.g., fibrotic conditions of the liver, lung, blood vessels, and / or eye, e.g., myocardial fibrosis and idiopathic pulmonary fibrosis (IPF)); metabolic diseases (e.g., type II diabetes and obesity); inflammatory diseases or conditions, autoimmune diseases, cardiovascular diseases (e.g., congestive heart failure and hypertension); ophthalmic diseases, e.g., age-related macular degeneration; pulmonary diseases, musculoskeletal diseases, skeletal diseases, neurological diseases, e.g., osteoporosis; wound healing; weight loss; and cancer (e.g., carcinoma, myeloma, osteoinductive loss cancer, pituitary cancer, and gastrointestinal cancer). In a further aspect, the present disclosure provides use of an ActRII binding protein provided herein in the manufacture of a medicament for the treatment or amelioration of one or more of the above diseases or conditions.

[0090] As used herein, "in combination with" or "combination therapy" refers to any form of administration in which an additional therapy (e.g., a second, third, fourth, etc.) is still effective in the body (e.g., multiple compounds may be effective in a subject simultaneously, including synergistic effects of the compounds). Efficacy may not correlate to measurable concentrations of the agent in blood, serum, or plasma. For example, different therapeutic compounds can be administered either in the same formulation or in separate formulations, either concomitantly or sequentially, and on different schedules. Thus, a subject receiving such treatment can benefit from the combined effects of the different therapies. One or more ActRII binding proteins of the present disclosure can be administered simultaneously with, prior to, or subsequent to one or more other additional agents and / or supportive therapies. Generally, each therapeutic agent is administered at a dose and / or time schedule determined for that particular agent. The particular combination to use in a regimen will take into account compatibility of the antagonists of the present disclosure with the treatment and / or the desired outcome.

[0091] The methods and techniques of the present disclosure are generally carried out according to known conventional methods, as described in various general and more specific references cited and described throughout this disclosure, unless otherwise indicated. See, for example, Sambrook et al., Molecular Cloning: A Laboratory Manual, 3rd ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY (2001), and Ausubel et al., Current Protocols in Molecular Biology, Greene Publishing Associates (1992), and Harlow and Lane Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY (1990); all of which are incorporated herein by reference.

[0092] The terms "cancer," "tumor," "cancerous," and "malignant" refer to or describe the physiological condition in mammals that is typically characterized by unregulated cell growth. Examples of cancer include, but are not limited to, carcinoma including adenocarcinoma, lymphoma, blastoma, melanoma, sarcoma, and leukemia. More specific examples of such cancers include squamous cell carcinoma, small cell lung cancer, non-small cell lung cancer, gastrointestinal cancer, Hodgkin's and non-Hodgkin's lymphoma, pancreatic cancer, glioblastoma, glioma, cervical cancer, ovarian cancer, liver cancer such as liver carcinoma and hepatocellular carcinoma, bladder cancer, breast cancer (including hormone-mediated breast cancer, see, e.g., Innes et al., Br. J. Cancer 94:1057-1065 (2006)), colon cancer, colorectal cancer, endometrial cancer, myeloma (such as multiple myeloma), salivary gland cancer, basal cell carcinoma, melanoma, prostate cancer, vulvar cancer, thyroid cancer, testicular cancer, esophageal cancer, various types of head and neck cancer, and cancers of mucinous origin such as mucinous ovarian cancer and bile duct cancer (liver). In certain aspects, the cancer is myelofibrosis, myeloma (e.g., multiple myeloma), or pituitary cancer. In another aspect, the cancer is breast cancer, gastrointestinal cancer, or carcinoma (e.g., basal and squamous cell carcinoma). In a further aspect, the cancer is a bone loss-inducing cancer.

[0093] The terms "polynucleotide" and "nucleic acid" are used interchangeably and are intended to encompass the singular as well as the plural forms of nucleic acid, and refer to an isolated nucleic acid molecule or construct, e.g., messenger RNA (mRNA), complementary DNA (cDNA), or plasmid DNA (pDNA). In certain aspects, a polynucleotide contains conventional phosphodiester bonds or non-conventional bonds (e.g., amide bonds as found in peptide nucleic acids (PNAs)). The term "nucleic acid" refers to any one or more nucleic acid segments, e.g., DNA, cDNA, or RNA fragments, present in a polynucleotide. When applied to a nucleic acid or polynucleotide, the term "isolated" refers to a nucleic acid molecule, DNA or RNA, that has been removed from its natural environment; for example, a recombinant polynucleotide encoding an antigen-binding protein contained in a vector is considered isolated for purposes of the present disclosure. Further examples of isolated polynucleotides include recombinant polynucleotides that are maintained in a heterologous host cell or that are purified (partially or substantially) from other polynucleotides in solution. Isolated RNA molecules include in vivo or in vitro RNA transcripts of the polynucleotides of the present disclosure. Isolated polynucleotides or nucleic acids according to the present disclosure further include such molecules produced synthetically. In addition, a polynucleotide or nucleic acid may include regulatory elements such as a promoter, an enhancer, a ribosomal binding site, or a transcription termination signal.

[0094] The term "vector" refers to a construct capable of delivering, and in some embodiments expressing, one or more genes or sequences of interest in a host cell. Examples of vectors include, but are not limited to, viral vectors, naked DNA or RNA expression vectors, plasmids, cosmids, or phage vectors, DNA or RNA expression vectors associated with cationic condensing agents, DNA or RNA expression vectors encapsulated in liposomes, and certain eukaryotic cells, such as producer cells.

[0095] The term "host cell" refers to a cell or population of cells that harbors or is capable of harboring a recombinant nucleic acid. Host cells can be prokaryotic (e.g., E. coli) or eukaryotic. Host cells can be fungal cells, including yeasts such as Saccharomyces cerevisiae, Pichia pastoris, or Schizosaccharomyces pombe. Host cells can also be any of a variety of animal cells, such as insect cells (e.g., Sf-9) or mammalian cells (e.g., HEK293F, CHO, COS-7, NIH-3T3, NS0, PER.C6®, and hybridoma). In a further aspect, host cells are CHO-K, CHO-0, CHO-Lec10, CHO-Lec13, CHO-Lec1, CHO Pro - 5, and CHO dhfr - In a particular embodiment, the host cell is a hybridoma.

[0096] The terms "polypeptide," "peptide," and "protein" are used interchangeably herein to refer to polymers of amino acids of any length. A polymer can be linear or branched, it can comprise modified amino acids, and it can be interrupted by non-amino acids. The term also encompasses amino acid polymers that are modified naturally or by intervention, such as disulfide bond formation, glycosylation, lipidation, acetylation, phosphorylation, or any other manipulation or modification, such as conjugation with a labeling component. Also included within this definition are polypeptides containing, for example, one or more analogs of an amino acid (including, for example, unnatural amino acids), as well as other modifications known in the art. In some aspects, the provided ActRII binding proteins are based on antibodies, and therefore it is understood that the ActRII binding proteins can occur as single chains or associated chains.

[0097] A "recombinant" polypeptide, protein, or antibody refers to a polypeptide, protein, or antibody produced by recombinant DNA techniques. Recombinantly produced polypeptides, proteins, and antibodies expressed in host cells are considered isolated for the purposes of this disclosure, as are naturally occurring or recombinant polypeptides that have been separated, fractionated, or partially or substantially purified by any suitable technique.

[0098] Also included in the present disclosure are fragments, variants, or derivatives of polypeptides, and any combination thereof. The term "fragment," when referring to polypeptides and proteins, includes any polypeptide or protein that retains at least some of the properties of the reference polypeptide or protein. Fragments of polypeptides include proteolytic fragments as well as deletion fragments.

[0099] The term "variant" refers to an antibody or polypeptide sequence that differs from that of a parent antibody or polypeptide sequence based on at least one amino acid modification. Antibody or polypeptide variants include fragments as well as antibodies or polypeptides with altered amino acid sequences due to amino acid substitutions, deletions, or insertions. Variants can be naturally occurring or non-naturally occurring. Non-naturally occurring variants can be produced using mutagenesis techniques known in the art. Variant polypeptides can contain conservative or non-conservative amino acid substitutions, deletions, or additions.

[0100] The term "derivative," when applied to an antibody or polypeptide, refers to an antibody or polypeptide that has been altered so as to exhibit additional properties not found in the native antibody or polypeptide. An example of a "derivative" antibody is a fusion or conjugate with a second polypeptide or another molecule (e.g., a polymer such as PEG, a chromophore, or a fluorophore) or atom (e.g., a radioisotope).

[0101] The term "amino acid substitution" refers to the replacement of an amino acid residue present in a parent sequence with another amino acid residue. Amino acids can be substituted in a parent sequence, for example, via chemical peptide synthesis or via known recombinant methods. Thus, a "substitution at position X" or a "substitution at position X" refers to the replacement of the amino acid present at position X with an alternative amino acid residue. In some embodiments, the substitution pattern can be described according to the schema AXY, where A is the single-letter code corresponding to the amino acid naturally present at position X, and Y is the substituting amino acid residue. In other aspects, the substitution pattern can be described according to the schema XY, where Y is the single-letter code corresponding to the amino acid residue substituting for the amino acid naturally present at position X.

[0102] A "conservative amino acid substitution" is one in which an amino acid residue is replaced with an amino acid residue having a similar side chain. Families of amino acid residues with similar side chains have been previously defined and include basic side chains (e.g., Lys, Arg, His), acidic side chains (e.g., Asp, Glu), uncharged polar side chains (e.g., Gly, Asp, Gln, Ser, Thr, Tyr, Cys), nonpolar side chains (e.g., Ala, Val, Leu, Ile, Pro, Phe, Met, Trp), β-branched side chains (e.g., Thr, Val, Ile), and aromatic side chains (e.g., Tyr, Phe, Trp, His). Thus, when an amino acid in a polypeptide is replaced with another amino acid from the same side chain family, the substitution is considered conservative. In another embodiment, stretches of amino acid residues can be conservatively replaced with structurally similar stretches that differ in the order and / or composition of side chain family members.

[0103] Non-conservative substitutions include (a) a residue having an electropositive side chain (e.g., Arg, His, or Lys) for or substituted by an electronegative residue (e.g., Glu or Asp); (b) a hydrophilic residue (e.g., Ser or Thr) for or substituted by a hydrophobic residue (e.g., Ala, Leu, Ile, Phe, or Val); (c) Cys or Pro for or substituted by any other residue; or (d) a residue having a bulky hydrophobic or aromatic side chain (e.g., Val, His, Ile, or Trp) for or substituted by one with a smaller side chain (e.g., Ala or Ser) or no side chain (e.g., Gly).

[0104] Other substitutions can be easily identified. For example, for the amino acid alanine, the substitution can be selected from any one of D-Ala, Gly, β-Ala, L-Cys, and D-Cys. For lysine, the substitution can be any one of D-Lys, Arg, D-Arg, homo-Arg, Met, D-Met, ornithine, or D-ornithine. In general, substitutions in functionally important regions that might be expected to cause changes in the properties of an isolated polypeptide are (a) a polar residue (e.g., Ser or Thr) substituted for (or by) a hydrophobic residue (e.g., Leu, Ile, Phe, or Ala); (b) a Cys residue substituted for (or by) any other residue; (c) a residue with an electropositive side chain (e.g., Lys, Arg, or His) substituted for (or by) a residue with an electronegative side chain (e.g., Glu or Asp); or (d) a residue with a bulky side chain (e.g., Phe) substituted for (or by) one without such a side chain (e.g., Gly). The likelihood that one of the aforementioned non-conservative substitutions will alter the functional properties of a protein also correlates with the location of the substitution relative to the functionally important regions of the protein: some non-conservative substitutions have little or no effect on biological properties.

[0105] The term "amino acid insertion" refers to the introduction of a new amino acid residue between two amino acid residues present in a parent sequence. Amino acids can be inserted into a parent sequence, for example, via chemical peptide synthesis or via recombinant methods known in the art. Thus, the phrase "insertion between positions X and Y" or "insertion between Kabat positions X and Y" (where X and Y correspond to amino acid positions) (e.g., insertion of a cysteine ​​amino acid residue between positions 239 and 240) refers to the insertion of an amino acid between positions X and Y, and also refers to the insertion of a codon encoding an amino acid between the codons encoding the amino acids at positions X and Y in a nucleic acid sequence.

[0106] The term "percent sequence identity" or "percent identity" between two polynucleotide or polypeptide sequences refers to the number of identical matching positions shared by the sequences over a comparison window, taking into account additions or deletions (i.e., gaps) that must be introduced for optimal alignment of the two sequences. A matching position is any position where the same nucleotide or amino acid is provided in both the target sequence and the reference sequence. Gaps provided in the target sequence are not counted because gaps are not nucleotides or amino acids. Similarly, gaps provided in the reference sequence are not counted because it is the nucleotides or amino acids in the target sequence that are counted, not the nucleotides or amino acids in the reference sequence. The percentage of sequence identity is calculated by determining the number of positions where identical amino acid residues or nucleic acid bases exist in both sequences to determine the number of matching positions, dividing the number of matching positions by the total number of positions in the comparison window, and multiplying the result by 100 to determine the percentage sequence identity. Comparison of sequences and determination of percent sequence identity between two sequences can be accomplished using readily available software programs. Suitable software programs are available from various sources for alignment of both protein and nucleotide sequences. One suitable program for determining percent sequence identity is bl2seq, which is part of the BLAST suite of programs available from the U.S. government's National Center for Biotechnology Information's BLAST website (blast.ncbi.nlm.nih.gov). bl2seq performs comparisons between two sequences using either the BLASTN or BLASTP algorithm. BLASTN is used to compare nucleic acid sequences, while BLASTP is used to compare amino acid sequences.Other suitable programs are, for example, Needle, Stretcher, Water, or Matcher, which are part of the EMBOSS bioinformatics program suite and are also available from the European Bioinformatics Institute (EBI), www.ebi.ac.uk / Tools / psa.

[0107] The structure for carrying the CDR or set of CDRs will generally be an antibody heavy or light chain sequence or substantial portion thereof, in which the CDR or set of CDRs is located at a position corresponding to the CDR or set of CDRs of naturally occurring VH and VL antibody variable domains encoded by a rearranged immunoglobulin gene. The structure and location of immunoglobulin variable domains and their CDRs can be readily determined by one of ordinary skill in the art using programs and known variable domain residue numbering systems such as Chothia, Chothia+, or Kabat (Kabat et al., Sequences of Proteins of Immunological Interest. 4th Edition. USDHHS. 1987, which is incorporated herein by reference in its entirety, and tools available on the Internet (e.g., at bioinf.org.uk / abysis / sequence_input / key_annotation / key_annotation.html; and immuno.bme.nwu.edu)).

[0108] CDRs can also be carried by other scaffolds such as fibronectin, cytochrome B, albumin (e.g., ALBUdAb (Domantis / GSK) and ALB-Kunitz (Dyax)), unstructured repeat sequences of 3 or 6 amino acids (e.g., PASylation® technology and XTEN® technology), and sequences containing elastin-like repeat domains (see, e.g., U.S. Patent Application No. 61 / 442,106, incorporated herein by reference in its entirety).

[0109] The CDR amino acid sequences substantially as set out herein may be carried as CDRs in a human variable domain or a substantial portion thereof. The HCDR3 sequences substantially as set out herein represent embodiments of the present disclosure, each of which may be carried as an HCDR3 in a human heavy chain variable domain or a substantial portion thereof.

[0110] The variable domains utilized in this disclosure can be derived from any germline or rearranged human variable domain, or can be synthetic variable domains based on consensus sequences of known human variable domains. CDR sequences (e.g., CDR3) can be introduced using recombinant DNA techniques into a repertoire of variable domains lacking a CDR (e.g., CDR3).

[0111] For example, Marks et al. (Bio / Technology 10:779-783 (1992), incorporated herein by reference in its entirety) provide a method for generating a repertoire of antibody variable domains in which a consensus primer directed to or adjacent to the 5' end of the variable domain region is used in conjunction with a consensus primer to the third framework region of a human VH gene to provide a repertoire of VH variable domains lacking CDR3. Marks et al. further describe how this repertoire can be combined with the CDR3 of a particular antibody. Using similar techniques, the CDR3-derived sequences of the present disclosure can be shuffled with a repertoire of VH or VL domains lacking CDR3, and the shuffled complete VH or VL domains can be combined with the cognate VL or VH domain to provide an antigen-binding protein. The repertoire can then be displayed in a suitable host system, such as the phage display systems described in International Application Publication No. WO 92 / 01047, or any of the many subsequent systems in the literature, including Kay et al., (1996) Phage Display of Peptides and Proteins: A Laboratory Manual, San Diego: Academic Press, so that suitable antigen-binding proteins can be selected. 4 More than 10 distinct members, e.g., 10 6 ~10 8 , or 10 10The host cell may consist of 10 or more members. Other suitable host systems include yeast display, bacterial display, T7 display, and ribosome display. For a review of ribosome display, see Lowe et al., Curr. Pharm. Biotech. 517-527 (2004) and International Application Publication No. WO 92 / 01047, each of which is incorporated herein by reference in its entirety. Similar shuffling or combinatorial techniques have also been described for β-lactamase genes by Stemmer (Nature 370:389-391 (1994) (incorporated herein by reference in its entirety)), who observed that the approach could be used for antibody generation.

[0112] An ActRII-binding protein (e.g., an anti-ActRIIA antibody and an anti-ActRIIB antibody) is said to "compete" with a reference molecule for binding to ActRII (e.g., ActRIIB and / or ActRIIA, respectively) if the ActRII-binding protein binds to ActRII to such an extent that the ActRII-binding protein blocks the binding of the reference molecule to ActRII to some extent. The ability of a protein to compete for binding to ActRII and thereby interfere with, block, or "cross-block" one anchor bound to ActRII can be determined by any standard competitive binding assay known in the art, including, for example, a competitive ELISA assay, surface plasmon resonance (SPR; BIACORE®, Biosensor, Piscataway, NJ), or according to the method described in Scatchard et al. (Ann. NY Acad. Sci. 51:660-672 (1949)). An ActRII binding protein is said to competitively inhibit the binding of a reference molecule to ActRII, for example, by at least 90%, at least 80%, at least 70%, at least 60%, or at least 50%. According to some embodiments, an ActRII binding protein competitively inhibits the binding of a reference molecule to ActRIIA, for example, by at least 90%, at least 80%, at least 70%, at least 60%, or at least 50%. According to other embodiments, an ActRII binding protein competitively inhibits the binding of a reference molecule to ActRIIB, for example, by at least 90%, at least 80%, at least 70%, at least 60%, or at least 50%.

[0113] ActRII-binding proteins A protein that specifically binds to ActRII is provided.

[0114] In some embodiments, the ActRII binding protein binds to ActRII with an affinity that is at least 100, 500, or 1000 times greater than the affinity of the ActRII binding protein for a control protein that is not a TGF-β receptor family member. In certain embodiments, the ActRII binding protein binds to ActRII and has a dissociation constant (K) of <1 μM, <100 nM, <10 nM, <1 nM, <0.1 nM, <10 pM, <1 pM, or <0.1 pM. D In some embodiments, the ActRII binding protein has a K for human ActRII within the range of ≦1 μM to ≧0.1 pM, ≦100 μM to ≧0.1 pM, or ≦100 μM to ≧1 pM. D It has.

[0115] In some embodiments, BIACORE® analysis is used to determine the ability of an ActRII binding protein (e.g., an anti-ActRII antibody) to compete / block binding to an ActRII protein by a reference ActRII binding protein (e.g., an anti-ActRII antibody). The BIACORE® instrument (e.g., a BIACORE® 3000) is operated according to the manufacturer's recommendations. In further embodiments, ActRII-Fc fusion proteins are captured on a CM5 BIACORE® chip with pre-bound anti-niFc IgG to generate an ActRII-coated surface. Typically, 200-800 resonance units of ActRII-Fc (dimer) are coupled to the chip (an amount that gives a readily measurable level of binding but is easily saturable by the concentration of test reagents used).

[0116] Two ActRII-binding proteins (A) to be assayed for their ability to compete / block each other * and B *ActRII binding proteins (denoted as A) are mixed in a 1:1 molar ratio of binding sites in a suitable buffer to form a test mixture. When calculating concentrations on a binding site basis, the molecular weight of an ActRII binding protein is assumed to be the total molecular weight of the ActRII binding protein divided by the number of ActRIIA binding sites on that ActRII binding protein. The concentration of each ActRII binding protein in the test mixture (i.e., A * and B * ) must be high enough to easily saturate the binding sites of the ActRII-binding protein for the ActRII-Fc molecules captured on the BIACORE® chip. * and B * are present at the same molar concentration (on a binding basis), which is typically between 1.00 and 1.5 micromolar (on a binding site basis). * alone and ActRII-binding protein B * Separate solutions containing only ActRII-binding protein A are also prepared. * and ActRII-binding protein B * ActRII-Fc must be present in the same buffer and at the same concentration as the test mixture. The test mixture is passed over an ActRII-Fc coated BIACORE® chip and the total amount of binding is recorded. The chip is then treated in a manner that removes bound ActRII binding protein without damaging the chip-bound ActRII-Fc. Typically, this is done by treating the chip with 30 mM HCl for 60 seconds. ActRII binding protein A is then added. * A single solution is passed over the ActRII-Fc coated surface and the amount of binding is recorded. The chip is again treated to remove the bound antibody without damaging the ActRII-Fc bound to the chip. ActRII binding protein B is then added. * The solution alone is passed over the ActRII-Fc coated surface and the amount of binding is recorded. * and ActRII-binding protein B *The maximum theoretical binding of the mixture is then calculated. This is the sum of the binding of each ActRII binding protein when passed alone over the ActRII surface. If the actual recorded binding of the mixture is lower than this theoretical maximum, then the two ActRII binding proteins are competing / blocking each other. Thus, generally, a blocking ActRII binding protein is one that binds to ActRII in the BIACORE® blocking assay described above such that during the assay and in the presence of the ActRII binding protein, the recorded binding is between 80% and 0.1% (e.g., 80% and 4%) of the theoretical maximum binding of the two ActRII binding proteins in combination, specifically between 75% and 0.1% (e.g., 75% and 4%) of the theoretical maximum binding, and more specifically between 70% and 0.1% (e.g., 70% and 4%) of the theoretical maximum binding (as defined immediately above).

[0117] The BIACORE® assay described above is an exemplary assay used to determine whether two ActRII-binding proteins, such as anti-ActRII antibodies, compete / block each other for binding to ActRII. In rare cases, a particular ActRII-binding protein may not bind to ActRII-Fc coupled to a CM5 BIACORE® chip via anti-Fc IgG (this can occur if the relevant binding site on ActRII is masked or destroyed by ActRII ligation to Fc). In such cases, blocking can be determined using a tagged version of ActRII (e.g., C-terminal His-tagged ActRII). In this particular format, an anti-His antibody is coupled to the BIACORE® chip, and then His-tagged ActRII is passed over the surface of the chip and captured by the anti-His antibody. Cross-blocking analysis is essentially performed as described above, except that after each chip regeneration cycle, new His-tagged ActRII is loaded back onto the surface coated with anti-His antibody. Furthermore, various other tag and tag-binding protein combinations known in the art can be used for such blocking analysis (e.g., HA tag and anti-HA antibody; FLAG tag and anti-FLAG antibody; biotin tag and streptavidin). The following generally describes an ELISA assay for determining whether an ActRII-binding protein blocks or can block the binding of a reference ActRII-binding protein to ActRII.

[0118] In some embodiments, ELISA is used to determine the ability of an ActRII binding protein (e.g., an anti-ActRII antibody) to compete with a reference ActRII binding protein (e.g., an anti-ActRII antibody or an ActRII ligand) for binding to an ActRII protein. The general principle of such an assay is that a reference ActRII binding protein (e.g., an anti-ActRII antibody) is coated onto the wells of an ELISA plate. An excess amount of a second, potentially blocking, test ActRII binding protein is added in solution (i.e., not bound to the ELISA plate). A limited amount of ActRII (or ActRII-Fc) is then added to the wells. The coated reference ActRII binding protein and the test ActRII binding protein in solution compete for binding of a limited number of ActRII (or ActRII-Fc) molecules. The plate is washed to remove ActRII not bound by the coated reference ActRII binding protein, the test solution-phase ActRII binding protein, and any complexes formed between the test solution-phase ActRII binding protein and ActRII. The amount of bound ActRII is then measured using an appropriate ActRII detection reagent. A test ActRII binding protein in solution that can block the binding of the coated reference ActRII binding protein to ActRII can cause a decrease in the number of ActRII molecules, because the coated reference ActRII binding protein can bind in proportion to the number of ActRII molecules that the coated reference ActRII binding protein could bind in the absence of the second solution-phase test ActRII binding protein. The background signal for the assay is defined as the signal obtained in wells with the coated reference ActRII binding protein, the solution-phase test ActRII binding protein, ActRII buffer only (i.e., no ActRII), and the ActRII detection reagent.The positive control signal for the assay is defined as the signal obtained in wells with coated reference ActRII binding protein, solution-phase test ActRII binding protein buffer only (i.e., no solution-phase test ActRII binding protein), ActRII, and ActRII detection reagent. The ELISA assay is performed in a format that has a positive control signal at least three times the background signal. As a control for methodological artifacts, cross-blocking assays can be performed in the format described immediately above or reversed (test ActRII binding protein as coated antibody and reference ActRII binding protein as solution-phase antibody).

[0119] In some embodiments, a reporter gene assay is used to determine the ability of an ActRII binding protein (e.g., an anti-ActRII antibody) to neutralize ActRII (e.g., ActRIIB). In some embodiments, a reporter gene assay is performed using recombinant A204 cells to determine the ability of an ActRII binding protein (e.g., an anti-ActRII antibody) to neutralize ActRII (e.g., ActRIIB) activity. The assay is based on a human rhabdomyosarcoma cell line transfected with a pGL3(CAGA)12 plasmid containing a (CAGA)12 motif (see, e.g., Dennler et al., EMBO 17:3091-3100 (1998) and U.S. Patent No. 8,765,385, each of which is incorporated herein by reference in its entirety) to control for transfection efficiency, and a ReniUa reporter plasmid (pRLCMV). Because the CAGA12 motif is present in a TGF-β response gene (PAI-1 gene), this vector is generally useful for factors that signal through Smad2 and Smad3. Regarding measuring the ActRIIB-binding activity of candidate proteins using this assay, the A204 cell line primarily expresses ActRIIA over ActRIIB, so antibodies cannot be directly tested for their potential ActRIIB-neutralizing ability. Instead, this assay is designed to detect the ability of test ActRII protein-binding candidates to neutralize the inhibitory effect of the soluble fusion protein ActRIIB-Fc on the activation of endogenous ActRIIA by ligands (e.g., activin A or GDF11) that can bind both ActRIIB and ActRIIA with high affinity. Thus, in this assay, ligand-mediated activation of ActRIIA occurs regardless of the presence of ActRIIB-Fc once ActRIIB binding is neutralized.

[0120] On the first day of the assay, A204 cells (ATCC HTB-82) were plated at 10 5On day 2, a solution containing 10 μg pGL3(CAGA)12, 1 μg pRLCMV, 30 μl Fugene 6 (Roche Diagnostics), and 970 μl OptiMEM (Invitrogen) was pre-incubated for 30 minutes and then added to McCoy's growth medium, which was then applied to the plated cells (500 μl / well) for overnight incubation at room temperature. On day 3, the medium was removed, and the cells were incubated for 6 hours at 37° C. with a mixture of ligands and inhibitors prepared as described below.

[0121] According to one embodiment, the neutralizing ability of an ActRII-binding protein, such as an anti-ActRII antibody, is assessed in a 200 μl volume of assay buffer (McCoy's medium + 0.1% BSA) by making serial dilutions of the test protein in a 48-well plate. In assays assessing the ability of a candidate protein to neutralize ActRIIB activity, an equal volume of ActRIIB-Fc (200 μg / ml) in assay buffer is then added. After incubating the test solution at 37° C. for 30 minutes, 400 μl of activin A (10 ng / ml) is added to all wells, and 350 μl of this mixture is added to each well of a 48-well plate of A204 cells. Each concentration of test protein is tested in duplicate. In assays assessing the ability of a candidate protein to neutralize ActRIIB activity, the final concentration of ActRIIB-Fc is 50 ng / ml (this is the IC50 for an inhibitor of activin A signaling when the final concentration of activin A is 5 ng / ml). 50After 6 hours of incubation with the test solution, the cells are rinsed with phosphate-buffered saline containing 0.1% BSA, then lysed with passive lysis buffer (Promega E1941) and stored overnight at -70°C. On the fourth and final day, the plates are warmed to room temperature with gentle agitation. Cell lysates are transferred in duplicate to chemiluminescence plates (96 wells) and analyzed in a luminometer with the Dual-Luciferase Reporter Assay system (Promega E1980) reagents to determine normalized luciferase activity.

[0122] The pharmacokinetic parameters that depend on ActRIIB signal transduction can be measured as the endpoint for the in vivo test of ActRIIB binding protein, in order to identify those binding proteins that can neutralize ActRIIB and provide therapeutic benefits.ActRIIB neutralizing binding agent is defined as one that can cause statistically significant changes in these pharmacokinetic parameters compared with vehicle-treated animals.This in vivo test can be carried out in any suitable mammal (for example, mouse, rat or monkey).

[0123] In some embodiments, the ActRII binding protein binds to ActRIIA with an affinity that is at least 100, 500, or 1000 times greater than the affinity of the ActRII binding protein for a control protein that is not a TGF-β receptor family member. In further embodiments, the ActRII binding protein binds to ActRIIA with an affinity that is at least 100, 500, or 1000 times greater than the affinity of the ActRII binding protein for a control protein that is not a TGF-β receptor family member. In certain embodiments, the ActRIIA binding protein binds to ActRIIA and has a dissociation constant (K) of <1 μM, <100 nM, <10 nM, <1 nM, <0.1 nM, <10 pM, <1 pM, or <0.1 pM. DIn some embodiments, the ActRIIA binding protein has a K for human ActRIIA within the range of ≦1 μM to ≧0.1 pM, ≦100 μM to ≧0.1 pM, or ≦100 μM to ≧1 pM. D It has.

[0124] In some embodiments, the ActRII binding protein binds to ActRIIB with an affinity that is at least 100, 500, or 1000 times greater than the affinity of the ActRII binding protein for a control protein that is not a TGF-β family member. In further embodiments, the ActRII binding protein binds to ActRIIB with an affinity that is at least 100, 500, or 1000 times greater than the affinity of the ActRII binding protein for a control protein that is not a TGF-β receptor family member. In certain embodiments, the ActRIIB binding protein binds to ActRIIB and has a dissociation constant (K) of <1 μM, <100 nM, <10 nM, <1 nM, <0.1 nM, <10 pM, <1 pM, or <0.1 pM. D In some embodiments, the ActRIIB binding protein has a K for human ActRIIB within the range of ≦1 μM to ≧0.1 pM, ≦100 μM to ≧0.1 pM, or ≦100 μM to ≧1 pM. D It has.

[0125] In some embodiments, the ActRII binding protein binds to ActRIIB and ActRIIA with an affinity that is at least 100, 500, or 1000 times greater than the affinity of the ActRII binding protein for a control protein that is not a TGF-β family member. In further embodiments, the ActRII binding protein binds to ActRIIB and ActRIIA with an affinity that is at least 100, 500, or 1000 times greater than the affinity of the ActRII binding protein for a control protein that is not a TGF-β receptor family member. In certain embodiments, the ActRII binding protein binds to ActRIIB and ActRIIA and has a dissociation constant (K) of <1 μM, <100 nM, <10 nM, <1 nM, <0.1 nM, <10 pM, <1 pM, or <0.1 pM. D In some embodiments, the ActRIIA and ActRIIB binding proteins have a K for human ActRIIB and ActRIIA within the range of ≦1 μM to ≧0.1 pM, ≦100 μM to ≧0.1 pM, or ≦100 μM to ≧1 pM. D It has.

[0126] In some embodiments, the ActRII binding protein is an antibody that specifically binds to ActRII. In further embodiments, the ActRII binding protein is a full-length anti-ActRIIA antibody or a full-length anti-ActRIIB antibody. In further embodiments, the antibody is a monoclonal antibody, a recombinant antibody, a human antibody, a humanized antibody, a chimeric antibody, a bispecific antibody, a multispecific antibody, or an ActRII-binding antibody fragment thereof. In further embodiments, the antibody specifically binds to ActRIIB and / or ActRIIA.

[0127] In some embodiments, ActRII binding proteins (eg, anti-ActRII antibodies and ActRII-binding antibody fragments) can bind to ActRII molecules across species.

[0128] The mature ActRIIA extracellular domain of human ActRIIA (SEQ ID NO: 138) differs from that of the mouse ActRIIA ortholog (Ref. P27038) by only two conserved amino acid substitutions (i.e., K19R and V72I). In a further aspect, the ActRII binding protein is capable of binding to human ActRIIA (hActRIIA) and mouse ActRIIA (murActRIIA). In certain aspects, the ActRII binding protein has a 10 nucleotide sequence determined by BIACORE® or KINEXA®. -8 Under M, 10 -9 Less than M or 10 -10 A dissociation constant or K less than M D In a further aspect, the anti-ActRIIA antibody has a K of <1 nM. D In a further aspect, the anti-ActRIIA antibody binds to ActRIIA with a K within single digits of 1 nM or within double digits of 1 nM (e.g., as determined by BIACORE® analysis). D In some embodiments, the ActRIIA binding protein binds to ActRIIA with a K for human ActRIIA within the range of ≦1 μM to ≧0.1 pM, ≦100 μM to ≧0.1 pM, or ≦100 μM to ≧1 pM. D It has.

[0129] The mature extracellular domain of human ActRIIB (SEQ ID NO: 139) differs from the corresponding sequence of the mouse ActRIIB ortholog (NCBI Reference Sequence NP031423) by only one amino acid substitution (i.e., A95P). In certain embodiments, the ActRII binding protein has a 10 -8 Under M, 10 -9 Less than M or 10 -10 A dissociation constant or K less than M DIn a further aspect, the anti-ActRIIB antibody has a K of <1 nM as determined by BIACORE® or KINEXA® analysis. D In a further embodiment, the anti-ActRIIB antibody binds to ActRIIB with a K within single digits of 1 nM or within double digits of 1 nM. D In some embodiments, the ActRIIB binding protein binds to ActRIIB with a K for human ActRIIB within the range of ≦1 μM to ≧0.1 pM, ≦100 μM to ≧0.1 pM, or ≦1 nM to ≧1 pM. D It has.

[0130] In some embodiments, the anti-ActRII antibody is an ActRII-binding antibody fragment. In some embodiments, the ActRII-binding antibody fragment is a Fab, Fab', F(ab')2, Fv fragment, diabody, or single-chain antibody molecule. In further embodiments, the ActRII antibody is an Fd, single-chain Fv (scFv), disulfide-linked Fv, V-NAR domain, IgNar, intrabody, IgGΔCH2, minibody, F(ab')3, tetrabody, triabody, diabody, single-domain antibody, DVD-Ig, Fcab, mAb 2 , (scFv)2, scFv-Fc, or bis-scFv.

[0131] In further embodiments, the ActRII binding protein is an antibody comprising a VH and a VL. In some embodiments, the anti-ActRII antibody further comprises a heavy chain constant region or a fragment thereof. In some embodiments, the antibody comprises a heavy chain immunoglobulin constant region selected from the group consisting of: (a) a human IgA constant region or a fragment thereof; (b) a human IgD constant region or a fragment thereof; (c) a human IgE constant domain or a fragment thereof; (d) a human IgG1 constant region or a fragment thereof; (e) a human IgG2 constant region or a fragment thereof; (f) a human IgG3 constant region or a fragment thereof; (g) a human IgG4 constant region or a fragment thereof; and (h) a human IgM constant region or a fragment thereof. In certain embodiments, the ActRII binding protein comprises a heavy chain constant region or a fragment thereof, e.g., a human IgG constant region or a fragment thereof. In further embodiments, the ActRII binding protein comprises a heavy chain immunoglobulin constant domain that has altered or is mutated to alter effector function and / or half-life.

[0132] In certain embodiments, the ActRII binding protein is an antibody comprising an IgG1 heavy chain constant region containing a mutation that reduces effector function (e.g., Idusogie et al., J. Immunol. 166:2571-2575 (2001); Sazinsky et al., PNAS USA 105:20167-20172 (2008); Davis et al., J. Rheumatol. 34:2204-2210 (2007); Bolt et al., Eur. J. Immunol. 23:403-411 (1993); Alegre et al., Transplantation 57:1537-1543 (1994); Xu et al., Cell Immunol. 200:16-26 (2000); Cole et al., Transplantation 68:563-571 (1999); Hutchins et al., PNAS USA 92:11980-11984 (1995); Reddy et al., J. Immunol. 164:1925-1933 (2000); WO97 / 11971, and WO07 / 106585; U.S. Application Publication No. 2007 / 0148167A1; McEarchern et al., Blood 109:1185-1192 (2007); Strohl, Curr. Op. Biotechnol. 20:685-691 (2009); and Kumagai et al., J. Clin. Pharmacol. 47:1489-1497 (2007) (each of which is incorporated herein by reference in its entirety).

[0133] In some embodiments, the heavy chain constant region or fragment thereof comprises one or more amino acid substitutions compared to a wild-type IgG constant domain, and the modified IgG has reduced ADCC compared to the half-life of an IgG with a wild-type IgG constant domain. Examples of Fc sequence engineering modifications contained in the provided antibodies that reduce ADCC include IgG1-K326W, E333S; IgG2-E333S; IgG1-N297A; IgG1-L234A, L235A; IgG2-V234A, G237A; IgG4-L235A, G237A, E318A; IgG4-S228P, L236E; IgG2-EU sequence 118-260; IgG 4—includes one or more modifications corresponding to EU sequence 261-447; IgG2—H268Q, V309L, A330S, A331S; IgG1—C220S, C226S, C229S, P238S; IgG1—C226S, C229S, E233P, L234V, L235A; and IgG1—L234F, L235E, P331S, where the numbering of the positions is according to the EU index as in Kabat.

[0134] In certain embodiments, the ActRII binding protein comprises a heavy chain immunoglobulin constant domain that has reduced or is mutated to have reduced CDC activity. In certain embodiments, the ActRII binding protein is an antibody comprising an IgG1 heavy chain constant region containing a mutation that reduces CDC activity (e.g., WO 97 / 11971 and WO 07 / 106585; U.S. Patent Application Publication No. 2007 / 0148167 A1; McEarchern et al., Blood 109:1185-1192 (2007); Hayden-Ledbetter et al., Clin. Cancer 15:2739-2746 (2009); Lazar et al., PNAS USA 103:4005-4010 (2006); Bruckheimer et al., Neoplasia 11:509-517 (2009); Strohl, Curr. Op. Biotechnol. 20:685-691 (2009); and Sazinsky et al., PNAS USA 105:20167-20172 (2008), each of which is incorporated herein by reference in its entirety. Examples of Fc sequence engineering modifications included in anti-ActRII antibodies that reduce CDC include one or more modifications corresponding to IgG1-S239D, A330L, I332E; IgG2 EU sequence 118-260; IgG4-EU sequence 261-447; IgG2-H268Q, V309L, A330S, A331S; IgG1-C226S, C229S, E233P, L234V, L235A; IgG1-L234F, L235E, P331S; and IgG1-C226S, P230S.

[0135] In a further aspect, the heavy chain constant region or fragment thereof comprises one or more amino acid substitutions compared to a wild-type IgG constant domain, and the modified IgG has an increased half-life compared to the half-life of an IgG having the wild-type IgG constant domain. For example, the IgG constant domain can comprise one or more amino acid substitutions of amino acid residues at positions 251-257, 285-290, 308-314, 385-389, and 428-436 (amino acid position numbering according to the EU index as described in Kabat). In certain embodiments, the IgG constant domain may comprise one or more of: a substitution of the amino acid at Kabat position 252 with Tyr, Phe, Trp, or Thr; a substitution of the amino acid at Kabat position 254 with Thr; a substitution of the amino acid at Kabat position 256 with Ser, Arg, Gln, Glu, Asp, or Thr; a substitution of the amino acid at Kabat position 257 with Leu; a substitution of the amino acid at Kabat position 309 with Pro; a substitution of the amino acid at Kabat position 311 with Ser; a substitution of the amino acid at Kabat position 428 with Thr, Leu, Phe, or Ser; a substitution of the amino acid at Kabat position 433 with Arg, Ser, Iso, Pro, or Gln; or a substitution of the amino acid at Kabat position 434 with Trp, Met, Ser, His, Phe, or Tyr. More specifically, the IgG constant domain may contain amino acid substitutions compared to a wild-type human IgG constant domain, including substitution of the amino acid at Kabat position 252 with Tyr, substitution of the amino acid at Kabat position 254 with Thr, and substitution of the amino acid at Kabat position 256 with Glu.

[0136] In a further embodiment, the ActRII binding protein is an antibody comprising a light chain immunoglobulin constant region. In a further embodiment, the antibody comprises a human Ig kappa constant region or a human Ig lambda constant region.

[0137] In some embodiments, the ActRII binding protein comprises a CDR set: VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2, and VL-CDR3, wherein the CDRs are present in the VH and VL pairs disclosed in Table 1. In a further embodiment, the ActRII binding protein comprises a set of CDRs, wherein the CDRs are present in a VH and VL pair selected from the group consisting of: (a) a VH sequence of SEQ ID NO: 2, 16, 22, 28, 34, or 40 and a VL sequence of SEQ ID NO: 9, wherein the protein binds to ActRIIB; (b) a VH sequence of SEQ ID NO: 63 or 77 and a VL having the amino acid sequence of SEQ ID NO: 70, wherein the protein binds to ActRIIB; (c) a VH sequence of SEQ ID NO: 45 or 57 and a VL sequence of SEQ ID NO: 50, wherein the protein binds to ActRIIB; (d) a VH sequence of SEQ ID NO: 84, 98, 105, 112, or 119 and a VL sequence of SEQ ID NO: 91, wherein the protein binds to ActRIIA; and (e) a VH sequence of SEQ ID NO: 125 and a VL sequence of SEQ ID NO: 132, wherein the protein binds to ActRIIA.

[0138] In a further embodiment, the ActRII binding protein comprises a set of CDRs, the CDRs being present in a VH and VL pair having (a) a VH sequence of SEQ ID NO: 144 and a VL sequence of SEQ ID NO: 151, and the protein binds to ActRIIB.

[0139] In a further embodiment, the ActRII binding protein comprises a set of CDRs, the CDRs being present in a VH and VL pair having (a) a VH sequence of SEQ ID NO: 165 and a VL sequence of SEQ ID NO: 172, and the protein binds to ActIIRA and ActRIIB.

[0140] In some aspects, an ActRII binding protein comprises a set of CDRs: (a) VH-CDR1, VH-CDR2, and VH-CDR3, or (b) VL-CDR1, VL-CDR2, and VL-CDR3, where the set of CDRs are identical to or have a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or fewer than 10 amino acid substitutions, deletions, and / or insertions from a reference set of CDRs disclosed herein. In further aspects, an ActRII binding protein comprises a set of CDRs where the set of CDRs are identical to or have a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or fewer than 10 amino acid substitutions, deletions, and / or insertions from a reference set of CDRs in a VH or VL sequence disclosed in Table 1.

[0141] In some embodiments, an ActRII binding protein comprises a set of CDRs: VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2, and VL-CDR3, where the set of CDRs are identical to or have a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or fewer than 10 amino acid substitutions, deletions, and / or insertions from a reference set of CDRs disclosed herein. In further embodiments, an ActRII binding protein comprises a set of CDRs, where the set of CDRs are identical to or have a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or fewer than 10 amino acid substitutions, deletions, and / or insertions from a reference set of CDRs in a VH or VL sequence disclosed in Table 1.

[0142] In a further aspect, the ActRII binding protein specifically binds to ActRII and comprises a set of CDRs: VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2, and VL-CDR3, wherein the set of CDRs is identical to the reference set of CDRs or has a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or fewer than 10 amino acid substitutions, deletions, and / or insertions from the reference set of CDRs. The reference set of CDRs includes (a) (i) VH-CDR1 having the amino acid sequence of SEQ ID NO: 3, 17, 23, 29, 35, or 41; (ii) VH-CDR2 having the amino acid sequence of SEQ ID NO: 4, 18, 24, 30, or 36; (iii) VH-CDR3 having the amino acid sequence of SEQ ID NO: 5; (iv) VL-CDR1 having the amino acid sequence of SEQ ID NO: 10; and (v) VL-CDR2 having the amino acid sequence of SEQ ID NO: 11. and (vi) VL-CDR3 has the amino acid sequence of SEQ ID NO: 12; the protein binds to ActRIIB; (b) (i) VH-CDR1 has the amino acid sequence of SEQ ID NO: 64 or 78; (ii) VH-CDR2 has the amino acid sequence of SEQ ID NO: 65 or 79; (iii) VH-CDR3 has the amino acid sequence of SEQ ID NO: 66 or 80; (iv) VL-CDR1 has the amino acid sequence of SEQ ID NO: 71; (i) VH-CDR1 has the amino acid sequence of SEQ ID NO: 3 or 58; (ii) VH-CDR2 has the amino acid sequence of SEQ ID NO: 4 or 59; (iii) VH-CDR3 has the amino acid sequence of SEQ ID NO: 46; (iv) VL-CDR1 is (v) VL-CDR2 has the amino acid sequence of SEQ ID NO: 52; and (vi) VL-CDR3 has the amino acid sequence of SEQ ID NO: 53; the protein binds to ActRIIB; (d) (i) VH-CDR1 has the amino acid sequence of SEQ ID NO: 85, 99, 106, or 113; (ii) VH-CDR2 has the amino acid sequence of SEQ ID NO: 86, 100, 107, 114, or 120;(iii) VH-CDR3 has the amino acid sequence of SEQ ID NO: 87, 101, 108, 115, or 121; (iv) VL-CDR1 has the amino acid sequence of SEQ ID NO: 92; (v) VL-CDR2 has the amino acid sequence of SEQ ID NO: 93; and (vi) VL-CDR3 has the amino acid sequence of SEQ ID NO: 94; the protein binds to ActRIIB and ActRIIA; or (e) (i) VH-CDR1 has the amino acid sequence of SEQ ID NO: 126; (ii) VH-CDR2 has the amino acid sequence of SEQ ID NO: 127; (iii) VH-CDR3 has the amino acid sequence of SEQ ID NO: 128; (iv) VL-CDR1 has the amino acid sequence of SEQ ID NO: 133; (v) VL-CDR2 has the amino acid sequence of SEQ ID NO: 134; and (vi) VL-CDR3 has the amino acid sequence of SEQ ID NO: 135; the protein binds to ActRIIA. In further aspects, the ActRIIB binding protein has at least one characteristic selected from the group consisting of: (a) competes with an ActRII ligand (e.g., activin A, activin B, GDF1, GDF3, GDF8 (myostatin), GDF11, BMP6, BMP7, BMP9, or BMP10) for binding to ActRII; (b) reduces phosphorylation of Smads (e.g., Smad2 and / or Smad3) in cells expressing ActRII in the presence of an ActRII ligand (e.g., activin A or GDF8); (c) reduces phosphorylation of ALK4 and / or ALK7 in cells expressing ActRII and ALK4 and / or ALK7 in the presence of an ActRII ligand; and (d) a K of ≦1 nM and ≧1 pM; D (e.g., as determined by BIACORE® analysis) binds to ActRII. In some embodiments, the ActRII binding protein has two, three, or four of the above characteristics. In some embodiments, the ActRII binding protein has at least two or at least three of the above characteristics.

[0143] In a further aspect, the ActRII binding protein specifically binds to ActRII and comprises a set of CDRs: VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2, and VL-CDR3, wherein the set of CDRs is identical to the reference set of CDRs or has a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or fewer than 10 amino acid substitutions, deletions, and / or insertions from the reference set of CDRs. The reference set of CDRs is (i) VH-CDR1 has the amino acid sequence of SEQ ID NO: 145; (ii) VH-CDR2 has the amino acid sequence of SEQ ID NO: 146; (iii) VH-CDR3 has the amino acid sequence of SEQ ID NO: 147; (iv) VL-CDR1 has the amino acid sequence of SEQ ID NO: 152; (v) VL-CDR2 has the amino acid sequence of SEQ ID NO: 153; and (vi) VL-CDR3 has the amino acid sequence of SEQ ID NO: 154; and the protein binds to ActRIIB. In a further aspect, the ActRIIB binding protein has at least one characteristic selected from the group consisting of: (a) competes with an ActRII ligand (e.g., activin A, activin B, GDF1, GDF3, GDF8 (myostatin), GDF11, BMP6, BMP7, BMP9, or BMP10) for binding to ActRII; (b) reduces phosphorylation of Smads (e.g., Smad2 and / or Smad3) in cells expressing ActRII in the presence of an ActRII ligand (e.g., activin A or GDF8); (c) reduces phosphorylation of ALK4 and / or ALK7 in cells expressing ActRII and ALK4 and / or ALK7 in the presence of an ActRII ligand; and (d) a K of ≦1 nM and ≧1 pM. D (e.g., as determined by BIACORE® analysis) binds to ActRII. In some embodiments, the ActRII binding protein has two, three, or four of the above characteristics. In some embodiments, the ActRII binding protein has at least two or at least three of the above characteristics.

[0144] In a further aspect, the ActRII binding protein specifically binds to ActRII and comprises a set of CDRs: VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2, and VL-CDR3, wherein the set of CDRs is identical to the reference set of CDRs or has a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or fewer than 10 amino acid substitutions, deletions, and / or insertions from the reference set of CDRs. The reference set of CDRs is (i) VH-CDR1 has the amino acid sequence of SEQ ID NO: 166; (ii) VH-CDR2 has the amino acid sequence of SEQ ID NO: 167; (iii) VH-CDR3 has the amino acid sequence of SEQ ID NO: 168; (iv) VL-CDR1 has the amino acid sequence of SEQ ID NO: 173; (v) VL-CDR2 has the amino acid sequence of SEQ ID NO: 174; and (vi) VL-CDR3 has the amino acid sequence of SEQ ID NO: 175; and the protein binds to ActIIRA and ActRIIB. In a further aspect, the ActRII binding protein has at least one characteristic selected from the group consisting of: (a) competes with an ActRII ligand (e.g., activin A, activin B, GDF1, GDF3, GDF8 (myostatin), GDF11, BMP6, BMP7, BMP9, or BMP10) for binding to ActRII; (b) reduces phosphorylation of Smads (e.g., Smad2 and / or Smad3) in cells expressing ActRII in the presence of an ActRII ligand (e.g., activin A or GDF8); (c) reduces phosphorylation of ALK4 and / or ALK7 in cells expressing ActRII and ALK4 and / or ALK7 in the presence of an ActRII ligand; and (d) a K of ≦1 nM and ≧1 pM. D (e.g., as determined by BIACORE® analysis) binds to ActRII. In some embodiments, the ActRII binding protein has two, three, or four of the above characteristics. In some embodiments, the ActRII binding protein has at least two or at least three of the above characteristics.

[0145] In some embodiments, an ActRII binding protein specifically binds ActRII and comprises a set of CDRs having a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, less than 10, or 0 amino acid substitutions, deletions, and / or insertions from a reference set of CDRs. The CDR set comprises: (a)(i) VH-CDR1 has the amino acid sequence of SEQ ID NO: 3; (ii) VH-CDR2 has the amino acid sequence of SEQ ID NO: 4; (iii) VH-CDR3 has the amino acid sequence of SEQ ID NO: 5; (iv) VL-CDR1 has the amino acid sequence of SEQ ID NO: 10; (v) VL-CDR2 has the amino acid sequence of SEQ ID NO: 11; and (vi) VL-CDR3 has the amino acid sequence of SEQ ID NO: 12; wherein the protein binds ActRIIB; and (b)(i) VH-CDR1 has the amino acid sequence of SEQ ID NO: 3; (ii) VH-CDR2 has the amino acid sequence of SEQ ID NO: 4; (iii) VH-CDR3 has the amino acid sequence of SEQ ID NO: 5; (iv) VL-CDR1 has the amino acid sequence of SEQ ID NO: 10; (v) VL-CDR2 has the amino acid sequence of SEQ ID NO: 11; and (vi) VL-CDR3 has the amino acid sequence of SEQ ID NO: 12. (ii) VH-CDR2 has the amino acid sequence of SEQ ID NO: 18; (iii) VH-CDR3 has the amino acid sequence of SEQ ID NO: 5; (iv) VL-CDR1 has the amino acid sequence of SEQ ID NO: 10; (v) VL-CDR2 has the amino acid sequence of SEQ ID NO: 11; and (vi) VL-CDR3 has the amino acid sequence of SEQ ID NO: 12; the protein binds to ActRIIB; (c)(i) VH-CDR1 has the amino acid sequence of SEQ ID NO: 23 (ii) VH-CDR2 has the amino acid sequence of SEQ ID NO: 24; (iii) VH-CDR3 has the amino acid sequence of SEQ ID NO: 5; (iv) VL-CDR1 has the amino acid sequence of SEQ ID NO: 10; (v) VL-CDR2 has the amino acid sequence of SEQ ID NO: 11; and (vi) VL-CDR3 has the amino acid sequence of SEQ ID NO: 12; the protein binds to ActRIIB; (d)(i) VH-CDR1 has the amino acid sequence of SEQ ID NO: 29; (ii) VH-CDR2 is (iii) VH-CDR3 has the amino acid sequence of SEQ ID NO: 5; (iv) VL-CDR1 has the amino acid sequence of SEQ ID NO: 10; (v) VL-CDR2 has the amino acid sequence of SEQ ID NO: 11; and (vi) VL-CDR3 has the amino acid sequence of SEQ ID NO: 12; the protein binds to ActRIIB; (e)(i) VH-CDR1 has the amino acid sequence of SEQ ID NO: 35; (ii) VH-CDR2 has the amino acid sequence of SEQ ID NO: 36;(iii) VH-CDR3 has the amino acid sequence of SEQ ID NO: 5; (iv) VL-CDR1 has the amino acid sequence of SEQ ID NO: 10; (v) VL-CDR2 has the amino acid sequence of SEQ ID NO: 11; and (vi) VL-CDR3 has the amino acid sequence of SEQ ID NO: 12; the protein binds to ActRIIB; (f)(i) VH-CDR1 has the amino acid sequence of SEQ ID NO: 41; (ii) VH-CDR2 has the amino acid sequence of SEQ ID NO: 18; (iii) VH-CDR3 has the amino acid sequence of SEQ ID NO: 5; (iv) VL-CDR1 is (v) VL-CDR2 has the amino acid sequence of SEQ ID NO: 11; and (vi) VL-CDR3 has the amino acid sequence of SEQ ID NO: 12; the protein binds to ActRIIB; (g) (i) VH-CDR1 has the amino acid sequence of SEQ ID NO: 64; (ii) VH-CDR2 has the amino acid sequence of SEQ ID NO: 65; (iii) VH-CDR3 has the amino acid sequence of SEQ ID NO: 66; (iv) VL-CDR1 has the amino acid sequence of SEQ ID NO: 71; and (v) VL-CDR2 has the amino acid sequence of SEQ ID NO: 72. and (vi) VL-CDR3 has the amino acid sequence of SEQ ID NO: 73; the protein binds to ActRIIB; and (h) (i) VH-CDR1 has the amino acid sequence of SEQ ID NO: 78; (ii) VH-CDR2 has the amino acid sequence of SEQ ID NO: 79; (iii) VH-CDR3 has the amino acid sequence of SEQ ID NO: 80; (iv) VL-CDR1 has the amino acid sequence of SEQ ID NO: 71; (v) VL-CDR2 has the amino acid sequence of SEQ ID NO: 72; and (vi) VL-CDR3 has the amino acid sequence of SEQ ID NO: 73; the protein binds to ActRIIB; and , binds to ActRIIB; (i)(i) VH-CDR1 has the amino acid sequence of SEQ ID NO: 3; (ii) VH-CDR2 has the amino acid sequence of SEQ ID NO: 4; (iii) VH-CDR3 has the amino acid sequence of SEQ ID NO: 46; (iv) VL-CDR1 has the amino acid sequence of SEQ ID NO: 51; (v) VL-CDR2 has the amino acid sequence of SEQ ID NO: 52; and (vi) VL-CDR3 has the amino acid sequence of SEQ ID NO: 53; the protein binds to ActRIIB; (j)(i) VH-CDR1 has the amino acid sequence of SEQ ID NO: 58;(ii) VH-CDR2 has the amino acid sequence of SEQ ID NO: 59; (iii) VH-CDR3 has the amino acid sequence of SEQ ID NO: 46; (iv) VL-CDR1 has the amino acid sequence of SEQ ID NO: 51; (v) VL-CDR2 has the amino acid sequence of SEQ ID NO: 52; and (vi) VL-CDR3 has the amino acid sequence of SEQ ID NO: 53; the protein binds to ActRIIB; (k)(i) VH-CDR1 has the amino acid sequence of SEQ ID NO: 85; (ii) VH-CDR2 has the amino acid sequence of SEQ ID NO: 86; and (iii) VH-CDR3 has the amino acid sequence (iv) VL-CDR1 has the amino acid sequence of SEQ ID NO: 92; (v) VL-CDR2 has the amino acid sequence of SEQ ID NO: 93; and (vi) VL-CDR3 has the amino acid sequence of SEQ ID NO: 94; the protein binds to ActRIIB and ActRIIA; (l)(i) VH-CDR1 has the amino acid sequence of SEQ ID NO: 99; (ii) VH-CDR2 has the amino acid sequence of SEQ ID NO: 100; (iii) VH-CDR3 has the amino acid sequence of SEQ ID NO: 101; (iv) VL-CDR1 has the amino acid sequence of SEQ ID NO: 92; (v) VL-CDR2 has the amino acid sequence of SEQ ID NO: 93; and (vi) VL-CDR3 has the amino acid sequence of SEQ ID NO: 94; the protein binds to ActRIIB and ActRIIA; (m) (i) VH-CDR1 has the amino acid sequence of SEQ ID NO: 106; (ii) VH-CDR2 has the amino acid sequence of SEQ ID NO: 107, and (iii) VH-CDR3 has the amino acid sequence of SEQ ID NO: 108; (iv) VL-CDR1 has the amino acid sequence of SEQ ID NO: 92; and (v) VL-CDR2 has the amino acid sequence of SEQ ID NO: 93. and (vi) VL-CDR3 has the amino acid sequence of SEQ ID NO: 94; the protein binds to ActRIIB and ActRIIA; (n) (i) VH-CDR1 has the amino acid sequence of SEQ ID NO: 113; (ii) VH-CDR2 has the amino acid sequence of SEQ ID NO: 114; (iii) VH-CDR3 has the amino acid sequence of SEQ ID NO: 115; (iv) VL-CDR1 has the amino acid sequence of SEQ ID NO: 92; (v) VL-CDR2 has the amino acid sequence of SEQ ID NO: 93; and (vi) VL-CDR3 has the amino acid sequence of SEQ ID NO: 94;(i) VH-CDR1 has the amino acid sequence of SEQ ID NO: 113; (ii) VH-CDR2 has the amino acid sequence of SEQ ID NO: 120; (iii) VH-CDR3 has the amino acid sequence of SEQ ID NO: 121; (iv) VL-CDR1 has the amino acid sequence of SEQ ID NO: 92; (v) VL-CDR2 has the amino acid sequence of SEQ ID NO: 93; and (vi) VL-CDR3 has the amino acid sequence of SEQ ID NO: 94; B and ActRIIA; or (p) (i) VH-CDR1 has the amino acid sequence of SEQ ID NO: 126; (ii) VH-CDR2 has the amino acid sequence of SEQ ID NO: 127; (iii) VH-CDR3 has the amino acid sequence of SEQ ID NO: 128; (iv) VL-CDR1 has the amino acid sequence of SEQ ID NO: 133; (v) VL-CDR2 has the amino acid sequence of SEQ ID NO: 134; and (vi) VL-CDR3 has the amino acid sequence of SEQ ID NO: 135; the protein binds to ActRIIA. In further aspects, the ActRIIB binding protein has at least one characteristic selected from the group consisting of: (a) competes with an ActRII ligand (e.g., activin A, activin B, GDF1, GDF3, GDF8 (myostatin), GDF11, BMP6, BMP7, BMP9, or BMP10) for binding to ActRII; (b) reduces phosphorylation of Smads (e.g., Smad2 and / or Smad3) in cells expressing ActRII in the presence of an ActRII ligand (e.g., activin A or GDF8); (c) reduces phosphorylation of ALK4 and / or ALK7 in cells expressing ActRII and ALK4 and / or ALK7 in the presence of an ActRII ligand; and (d) a K of ≦1 nM and ≧1 pM; D (e.g., as determined by BIACORE® analysis) binds to ActRII. In some embodiments, the ActRII binding protein has two, three, or four of the above characteristics. In some embodiments, the ActRII binding protein has at least two or at least three of the above characteristics.

[0146] In some aspects, the ActRII binding protein specifically binds to ActRIIB and comprises a set of CDRs: VH-CDR1, VH-CDR2, and VH-CDR3, wherein the set of CDRs is identical to the reference set of CDRs or has a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or fewer than 10 amino acid substitutions, deletions, and / or insertions from the reference set of CDRs. The reference set of CDRs is (a) (i) VH-CDR1 has the amino acid sequence of SEQ ID NO: 3, 17, 23, 29, 35, or 41; (ii) VH-CDR2 has the amino acid sequence of SEQ ID NO: 4, 18, 24, 30, or 36; and (iii) VH-CDR3 has the amino acid sequence of SEQ ID NO: 5; (b) (i) VH-CDR1 has the amino acid sequence of SEQ ID NO: 3 or 58; (ii) VH-CDR2 has the amino acid sequence of SEQ ID NO: 4 or 59; and (iii) VH-CDR3 has the amino acid sequence of SEQ ID NO: 46; or (c) (i) VH-CDR1 has the amino acid sequence of SEQ ID NO: 64 or 78; (ii) VH-CDR2 has the amino acid sequence of SEQ ID NO: 65 or 79; and (iii) VH-CDR3 has the amino acid sequence of SEQ ID NO: 66 or 80. In a further aspect, the ActRIIB binding protein has at least one characteristic selected from the group consisting of: (a) competes with an ActRII ligand (e.g., activin A, activin B, GDF1, GDF3, GDF8 (myostatin), GDF11, BMP6, BMP7, BMP9, or BMP10) for binding to ActRIIB; (b) reduces phosphorylation of Smads (e.g., Smad2 and / or Smad3) in cells expressing ActRIIB in the presence of an ActRIIB ligand (e.g., activin A or GDF8); (c) reduces phosphorylation of ALK4 and / or ALK7 in cells expressing ActRIIB and ALK4 and / or ALK7 in the presence of an ActRIIB ligand; and (d) a K of ≦1 nM and ≧1 pM. D(e.g., as determined by BIACORE® analysis) binds to ActRIIB. In some embodiments, the ActRIIB-binding protein has two, three, or four of the above characteristics. In some embodiments, the ActRIIB-binding protein has at least two or at least three of the above characteristics.

[0147] In some embodiments, the ActRII binding protein specifically binds ActRIIB and comprises a set of CDRs: VH-CDR1, VH-CDR2, and VH-CDR3, wherein the set of CDRs is identical to or has a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or fewer than 10 amino acid substitutions, deletions, and / or insertions from the reference set of CDRs. The reference set of CDRs is such that (a)(i) VH-CDR1 has the amino acid sequence of SEQ ID NO: 3; (ii) VH-CDR2 has the amino acid sequence of SEQ ID NO: 4; (iii) VH-CDR3 has the amino acid sequence of SEQ ID NO: 5; the protein binds ActRIIB; and (b)(i) VH-CDR1 has the amino acid sequence of SEQ ID NO: 17; (ii) VH-CDR2 has the amino acid sequence of SEQ ID NO: 18; and (iii) VH-CDR3 has the amino acid sequence of SEQ ID NO: 5. (c) (i) VH-CDR1 has the amino acid sequence of SEQ ID NO: 23; (ii) VH-CDR2 has the amino acid sequence of SEQ ID NO: 24; (iii) VH-CDR3 has the amino acid sequence of SEQ ID NO: 5; the protein binds to ActRIIB; (d) (i) VH-CDR1 has the amino acid sequence of SEQ ID NO: 29; (ii) VH-CDR2 has the amino acid sequence of SEQ ID NO: 30; (iii) (e) (i) VH-CDR1 has the amino acid sequence of SEQ ID NO: 35; (ii) VH-CDR2 has the amino acid sequence of SEQ ID NO: 36; (iii) VH-CDR3 has the amino acid sequence of SEQ ID NO: 5; the protein binds to ActRIIB; (f) (i) VH-CDR1 has the amino acid sequence of SEQ ID NO: 41; (ii) VH-CDR2 has the amino acid sequence of SEQ ID NO: 1 (iii) VH-CDR3 has the amino acid sequence of SEQ ID NO: 5; wherein the protein binds to ActRIIB; (g)(i) VH-CDR1 has the amino acid sequence of SEQ ID NO: 64; (ii) VH-CDR2 has the amino acid sequence of SEQ ID NO: 65; (iii) VH-CDR3 has the amino acid sequence of SEQ ID NO: 66; wherein the protein binds to ActRIIB; (h)(i) VH-CDR1 has the amino acid sequence of SEQ ID NO: 78;(ii) VH-CDR2 has the amino acid sequence of SEQ ID NO: 79; (iii) VH-CDR3 has the amino acid sequence of SEQ ID NO: 80; the protein binds to ActRIIB; (i)(i) VH-CDR1 has the amino acid sequence of SEQ ID NO: 3; (ii) VH-CDR2 has the amino acid sequence of SEQ ID NO: 4; (iii) VH-CDR3 has the amino acid sequence of SEQ ID NO: 46; the protein binds to ActRIIB; or (j)(i) VH-CDR1 has the amino acid sequence of SEQ ID NO: 58; (ii) VH-CDR2 has the amino acid sequence of SEQ ID NO: 59; (iii) VH-CDR3 has the amino acid sequence of SEQ ID NO: 46; the protein binds to ActRIIB. In further aspects, the ActRIIB binding protein has at least one characteristic selected from the group consisting of: (a) competes with an ActRII ligand (e.g., activin A, activin B, GDF1, GDF3, GDF8 (myostatin), GDF11, BMP6, BMP7, BMP9, or BMP10) for binding to ActRIIB; (b) reduces phosphorylation of Smads (e.g., Smad2 and / or Smad3) in cells expressing ActRIIB in the presence of an ActRIIB ligand (e.g., activin A or GDF8); (c) reduces phosphorylation of ALK4 and / or ALK7 in cells expressing ActRIIB and ALK4 and / or ALK7 in the presence of an ActRIIB ligand; and (d) a K of ≦1 nM and ≧1 pM; D (e.g., as determined by BIACORE® analysis) binds to ActRIIB. In some embodiments, the ActRIIB-binding protein has two, three, or four of the above characteristics. In some embodiments, the ActRIIB-binding protein has at least two or at least three of the above characteristics.

[0148] In some embodiments, the ActRII binding protein specifically binds to ActRIIB and comprises a set of CDRs: VL-CDR1, VL-CDR2, and VL-CDR3, wherein the set of CDRs is identical to a reference set of CDRs or has a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or fewer than 10 amino acid substitutions, deletions, and / or insertions from the reference set of CDRs. The reference set of CDRs is (a) (i) VL-CDR1 has the amino acid sequence of SEQ ID NO: 10; (ii) VL-CDR2 has the amino acid sequence of SEQ ID NO: 11; and (iii) VL-CDR3 has the amino acid sequence of SEQ ID NO: 12; the protein binds to ActRIIB; (b) (i) VL-CDR1 has the amino acid sequence of SEQ ID NO: 71; (ii) VL-CDR2 has the amino acid sequence of SEQ ID NO: 72; and (iii) VL-CDR3 has the amino acid sequence of SEQ ID NO: 73; the protein binds to ActRIIB; or (c) (i) VL-CDR1 has the amino acid sequence of SEQ ID NO: 51; (ii) VL-CDR2 has the amino acid sequence of SEQ ID NO: 52; and (iii) VL-CDR3 has the amino acid sequence of SEQ ID NO: 53; the protein binds to ActRIIB. In a further aspect, the ActRIIB binding protein has at least one characteristic selected from the group consisting of: (a) competes with an ActRII ligand (e.g., activin A, activin B, GDF1, GDF3, GDF8 (myostatin), GDF11, BMP6, BMP7, BMP9, or BMP10) for binding to ActRIIB; (b) reduces phosphorylation of Smads (e.g., Smad2 and / or Smad3) in cells expressing ActRIIB in the presence of an ActRIIB ligand (e.g., activin A or GDF8); (c) reduces phosphorylation of ALK4 and / or ALK7 in cells expressing ActRIIB and ALK4 and / or ALK7 in the presence of an ActRIIB ligand; and (d) a K of ≦1 nM and ≧1 pM. D(e.g., as determined by BIACORE® analysis) binds to ActRIIB. In some embodiments, the ActRIIB-binding protein has two, three, or four of the above characteristics. In some embodiments, the ActRIIB-binding protein has at least two or at least three of the above characteristics.

[0149] In some embodiments, the ActRII binding protein specifically binds ActRIIB and ActRIIA and comprises a set of CDRs: VH-CDR1, VH-CDR2, and VH-CDR3, wherein the set of CDRs is identical to or has a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or fewer than 10 amino acid substitutions, deletions, and / or insertions from the reference set of CDRs. The reference set of CDRs has VH-CDR1 having the amino acid sequence of SEQ ID NO: 85, 99, 106, or 113; VH-CDR2 having the amino acid sequence of SEQ ID NO: 86, 100, 107, 114, or 120; and VH-CDR3 having the amino acid sequence of SEQ ID NO: 87, 101, 108, 115, or 121. In a further aspect, the ActRIIB and ActRIIA binding proteins have at least one characteristic selected from the group consisting of: (a) compete with an ActRII ligand (e.g., activin A, activin B, GDF1, GDF3, GDF8 (myostatin), GDF11, BMP6, BMP7, BMP9, or BMP10) for binding to ActRIIB and / or ActRIIA; (b) compete with an ActRIIB and / or ActRIIA ligand (e.g., activin A, activin B, GDF1, GDF3, GDF8 (myostatin), GDF11, BMP6, BMP7, BMP9, or BMP10) for binding to ActRIIB and / or ActRIIA; (c) reducing the phosphorylation of Smads (e.g., Smad2 and / or Smad3) in cells expressing ActRIIB and / or ActRIIA in the presence of an ActRIIB and / or ActRIIA ligand (e.g., activin A or GDF8); (d) reducing the phosphorylation of ALK4 and / or ALK7 in cells expressing ActRIIB and / or ActRIIA and ALK4 and / or ALK7 in the presence of an ActRIIB and / or ActRIIA ligand; and (e) a K of ≦1 nM and ≧1 pM. D(e.g., as determined by BIACORE® analysis) binds to ActRIIB and / or ActRIIA. In some embodiments, the ActRIIB and / or ActRIIA binding protein has two, three, or four of the above characteristics. In some embodiments, the ActRIIB and / or ActRIIA binding protein has at least two or at least three of the above characteristics.

[0150] In some aspects, the ActRII binding protein specifically binds to ActRIIB and ActRIIA and comprises a set of CDRs: VH-CDR1, VH-CDR2, and VH-CDR3, wherein the set of CDRs is identical to the reference set of CDRs or has a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or fewer than 10 amino acid substitutions, deletions, and / or insertions from the reference set of CDRs. The reference set of CDRs is (a) (i) VH-CDR1 has the amino acid sequence of SEQ ID NO: 85; (ii) VH-CDR2 has the amino acid sequence of SEQ ID NO: 86; (iii) VH-CDR3 has the amino acid sequence of SEQ ID NO: 87; the protein binds to ActRIIB and ActRIIA; (b) (i) VH-CDR1 has the amino acid sequence of SEQ ID NO: 99; (ii) VH-CDR2 has the amino acid sequence of SEQ ID NO: 100; (iii) VH-CDR3 has the amino acid sequence of SEQ ID NO: 101; the protein binds to ActRIIB and ActRIIA; (c) (i) VH-CDR1 has the amino acid sequence of SEQ ID NO: 106; (ii) VH-CDR2 has the amino acid sequence of SEQ ID NO: 107 and (iii) VH-CDR3 has the amino acid sequence of SEQ ID NO: 108; the protein binds to ActRIIB and ActRIIA; (d) (i) VH-CDR1 has the amino acid sequence of SEQ ID NO: 113; (ii) VH-CDR2 has the amino acid sequence of SEQ ID NO: 114; (iii) VH-CDR3 has the amino acid sequence of SEQ ID NO: 115; the protein binds to ActRIIB and ActRIIA; or (e) (i) VH-CDR1 has the amino acid sequence of SEQ ID NO: 113; (ii) VH-CDR2 has the amino acid sequence of SEQ ID NO: 120; (iii) VH-CDR3 has the amino acid sequence of SEQ ID NO: 121; the protein binds to ActRIIB and ActRIIA.In a further aspect, the ActRII binding protein has at least one characteristic selected from the group consisting of: (a) competing with an ActRII ligand (e.g., activin A, activin B, GDF1, GDF3, GDF8 (myostatin), GDF11, BMP6, BMP7, BMP9, or BMP10) for binding to ActRIIB and / or ActRIIA; (b) reducing phosphorylation of Smads (e.g., Smad2 and / or Smad3) in cells expressing ActRIIB and / or ActRIIA in the presence of an ActRIIB and / or ActRIIA ligand (e.g., activin A or GDF8); (c) reducing phosphorylation of ALK4 and / or ALK7 in cells expressing ActRIIB and / or ActRIIA and ALK4 and / or ALK7 in the presence of an ActRIIB and / or ActRIIA ligand; and (d) a K of ≦1 nM and ≧1 pM. D (e.g., as determined by BIACORE® analysis) binds to ActRIIB and / or ActRIIA. In some embodiments, the ActRIIB and / or ActRIIA binding protein has two, three, or four of the above characteristics. In some embodiments, the ActRIIB and / or ActRIIA binding protein has at least two or at least three of the above characteristics.

[0151] In some embodiments, the ActRII binding protein specifically binds to ActRIIB and ActRIIA and comprises a set of CDRs: VL-CDR1, VL-CDR2, and VL-CDR3, wherein the set of CDRs is identical to the reference set of CDRs or has a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or less than 10 amino acid substitutions, deletions, and / or insertions from the reference set of CDRs. The reference set of CDRs includes: (i) VL-CDR1 having the amino acid sequence of SEQ ID NO: 92; (ii) VL-CDR2 having the amino acid sequence of SEQ ID NO: 93; and (iii) VL-CDR3 having the amino acid sequence of SEQ ID NO: 94; and the protein binds to ActRIIB and ActRIIA. In a further aspect, the ActRII binding protein has at least one characteristic selected from the group consisting of: (a) competing with an ActRII ligand (e.g., activin A, activin B, GDF1, GDF3, GDF8 (myostatin), GDF11, BMP6, BMP7, BMP9, or BMP10) for binding to ActRIIB and / or ActRIIA; (b) reducing phosphorylation of Smads (e.g., Smad2 and / or Smad3) in cells expressing ActRIIB and / or ActRIIA in the presence of an ActRIIB and / or ActRIIA ligand (e.g., activin A or GDF8); (c) reducing phosphorylation of ALK4 and / or ALK7 in cells expressing ActRIIB and / or ActRIIA and ALK4 and / or ALK7 in the presence of an ActRIIB and / or ActRIIA ligand; and (d) a K of ≦1 nM and ≧1 pM. D (e.g., as determined by BIACORE® analysis) binds to ActRIIB and / or ActRIIA. In some embodiments, the ActRIIB and / or ActRIIA binding protein has two, three, or four of the above characteristics. In some embodiments, the ActRIIB and / or ActRIIA binding protein has at least two or at least three of the above characteristics.

[0152] In some embodiments, the ActRII binding protein specifically binds ActRIIA and comprises a set of CDRs: VH-CDR1, VH-CDR2, and VH-CDR3, where the set of CDRs is identical to the reference set of CDRs or has a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or fewer than 10 amino acid substitutions, deletions, and / or insertions from the reference set of CDRs. The reference set of CDRs has VH-CDR1 having the amino acid sequence of SEQ ID NO: 126; VH-CDR2 having the amino acid sequence of SEQ ID NO: 127; and VH-CDR3 having the amino acid sequence of SEQ ID NO: 128. In a further aspect, the ActRIIA binding protein has at least one characteristic selected from the group consisting of: (a) competing with an ActRIIA ligand (e.g., activin A, activin B, GDF1, GDF3, or Nodal); (b) reducing phosphorylation of Smads (e.g., Smad2 and / or Smad3) in cells expressing ActRIIA in the presence of an ActRIIA ligand (e.g., activin A); (c) reducing phosphorylation of ALK4 and / or ALK7 in cells expressing ActRIIA and ALK4 and / or ALK7 in the presence of an ActRIIA ligand; and (d) a K of ≦1 nM and ≧1 pM. D (e.g., as determined by BIACORE® analysis) binds to ActRIIA. In some embodiments, the ActRIIA binding protein has two, three, or four of the above characteristics. In some embodiments, the ActRIIA binding protein has at least two or at least three of the above characteristics.

[0153] In some embodiments, the ActRII binding protein specifically binds to ActRIIA and comprises a set of CDRs: VL-CDR1, VL-CDR2, and VL-CDR3, where the set of CDRs is identical to the reference set of CDRs or has a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or fewer than 10 amino acid substitutions, deletions, and / or insertions from the reference set of CDRs. The reference set of CDRs has VL-CDR1 having the amino acid sequence of SEQ ID NO: 133; VL-CDR2 having the amino acid sequence of SEQ ID NO: 134; and VL-CDR3 having the amino acid sequence of SEQ ID NO: 135. In a further aspect, the ActRIIA binding protein has at least one characteristic selected from the group consisting of: (a) competing with an ActRIIA ligand (e.g., activin A, activin B, GDF1, GDF3, or Nodal); (b) reducing phosphorylation of Smads (e.g., Smad2 and / or Smad3) in cells expressing ActRIIA in the presence of an ActRIIA ligand (e.g., activin A); (c) reducing phosphorylation of ALK4 and / or ALK7 in cells expressing ActRIIA and ALK4 and / or ALK7 in the presence of an ActRIIA ligand; and (d) a K of ≦1 nM and ≧1 pM. D (e.g., as determined by BIACORE® analysis) binds to ActRIIA. In some embodiments, the ActRIIA binding protein has two, three, or four of the above characteristics. In some embodiments, the ActRIIA binding protein has at least two or at least three of the above characteristics.

[0154] In a further aspect, the ActRII binding protein specifically binds to ActRIIB and comprises a CDR set: VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2, and VL-CDR3, wherein the CDR set is identical to the reference set of CDRs or has a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or fewer than 10 amino acid substitutions, deletions, and / or insertions from the reference set of CDRs. The reference set of CDRs includes (a) (i) VH-CDR1 having the amino acid sequence of SEQ ID NO: 3, 17, 23, 29, 35, or 41; (ii) VH-CDR2 having the amino acid sequence of SEQ ID NO: 4, 18, 24, 30, or 36; (iii) VH-CDR3 having the amino acid sequence of SEQ ID NO: 5; (iv) VL-CDR1 having the amino acid sequence of SEQ ID NO: 10; (v) VL-CDR2 having the amino acid sequence of SEQ ID NO: 11; or (vi) VL-CDR3 having the amino acid sequence of SEQ ID NO: 12; (b) (i) VH-CDR1 having the amino acid sequence of SEQ ID NO: 3 or 58; (ii) VH-CDR2 having the amino acid sequence of SEQ ID NO: 4 or 59; (iv) VL-CDR1 has the amino acid sequence of SEQ ID NO: 51; (v) VL-CDR2 has the amino acid sequence of SEQ ID NO: 52; or (vi) VL-CDR3 has the amino acid sequence of SEQ ID NO: 53; or (c)(i) VH-CDR1 has the amino acid sequence of SEQ ID NO: 64 or 78; (ii) VH-CDR2 has the amino acid sequence of SEQ ID NO: 65 or 79; (iii) VH-CDR3 has the amino acid sequence of SEQ ID NO: 66 or 80; (iv) VL-CDR1 has the amino acid sequence of SEQ ID NO: 71; (v) VL-CDR2 has the amino acid sequence of SEQ ID NO: 72; or (vi) VL-CDR3 has the amino acid sequence of SEQ ID NO: 73. In a further aspect, the ActRIIB binding protein comprises a VH and a VL.In a further aspect, the ActRIIB binding protein has at least one characteristic selected from the group consisting of: (a) competes with an ActRII ligand (e.g., activin A, activin B, GDF1, GDF3, GDF8 (myostatin), GDF11, BMP6, BMP7, BMP9, or BMP10) for binding to ActRIIB; (b) reduces phosphorylation of Smads (e.g., Smad2 and / or Smad3) in cells expressing ActRIIB in the presence of an ActRIIB ligand (e.g., activin A or GDF8); (c) reduces phosphorylation of ALK4 and / or ALK7 in cells expressing ActRIIB and ALK4 and / or ALK7 in the presence of an ActRIIB ligand; and (d) a K of ≦1 nM and ≧1 pM. D (e.g., as determined by BIACORE® analysis) binds to ActRIIB. In some embodiments, the ActRIIB-binding protein has two, three, or four of the above characteristics. In some embodiments, the ActRIIB-binding protein has at least two or at least three of the above characteristics.

[0155] In a further aspect, the ActRII binding protein specifically binds ActRIIB and comprises a CDR set: VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2, and VL-CDR3, wherein the CDR set is: (a) (i) VH-CDR1 has the amino acid sequence of SEQ ID NO: 3, 17, 23, 29, 35, or 41; (ii) VH-CDR2 has the amino acid sequence of SEQ ID NO: 4, 18, 24, 30, or 36; (iii) VH-CDR3 has the amino acid sequence of SEQ ID NO: 5; (iv) VL-CDR1 has the amino acid sequence of SEQ ID NO: 10; (v) VL-CDR2 has the amino acid sequence of SEQ ID NO: 11; or (vi) VL-CDR3 has the amino acid sequence of SEQ ID NO: 12; (b) (i) VH-CDR1 has the amino acid sequence of SEQ ID NO: 3 or 58; (ii) VH-CDR2 has the amino acid sequence of SEQ ID NO: 4 or 59; (iii) VH-CDR3 has the amino acid sequence of SEQ ID NO: 46; (iv) VL-CDR1 has the amino acid sequence of SEQ ID NO: 51; (v) VL-CDR2 has the amino acid sequence of SEQ ID NO: 52; or (vi) VL-CDR3 has the amino acid sequence of SEQ ID NO: 53; or (c) (i) VH-CDR1 has the amino acid sequence of SEQ ID NO: 64 or 78; (ii) VH-CDR2 has the amino acid sequence of SEQ ID NO: 65 or 79; (iii) VH-CDR3 has the amino acid sequence of SEQ ID NO: 66 or 80; (iv) VL-CDR1 has the amino acid sequence of SEQ ID NO: 71; (v) VL-CDR2 has the amino acid sequence of SEQ ID NO: 72; or (vi) VL-CDR3 has the amino acid sequence of SEQ ID NO: 73. In a further aspect, the ActRIIB-binding protein comprises a VH and a VL.In a further aspect, the ActRIIB binding protein has at least one characteristic selected from the group consisting of: (a) competes with an ActRII ligand (e.g., activin A, activin B, GDF1, GDF3, GDF8 (myostatin), GDF11, BMP6, BMP7, BMP9, or BMP10) for binding to ActRIIB; (b) reduces phosphorylation of Smads (e.g., Smad2 and / or Smad3) in cells expressing ActRIIB in the presence of an ActRIIB ligand (e.g., activin A or GDF8); (c) reduces phosphorylation of ALK4 and / or ALK7 in cells expressing ActRIIB and ALK4 and / or ALK7 in the presence of an ActRIIB ligand; and (d) a K of ≦1 nM and ≧1 pM. D (e.g., as determined by BIACORE® analysis) binds to ActRIIB. In some embodiments, the ActRIIB-binding protein has two, three, or four of the above characteristics. In some embodiments, the ActRIIB-binding protein has at least two or at least three of the above characteristics.

[0156] In a further aspect, the ActRII binding protein specifically binds to ActRIIB and ActRIIA and comprises a CDR set: VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2, and VL-CDR3, wherein the CDR set is identical to the reference set of CDRs or has a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or fewer than 10 amino acid substitutions, deletions, and / or insertions from the reference set of CDRs. The reference set of CDRs has (a) VH-CDR1 having the amino acid sequence of SEQ ID NO: 85, 99, 106, or 113; (b) VH-CDR2 having the amino acid sequence of SEQ ID NO: 86, 100, 107, 114, or 120; (c) VH-CDR3 having the amino acid sequence of SEQ ID NO: 87, 101, 108, 115, or 121; (d) VL-CDR1 having the amino acid sequence of SEQ ID NO: 92; (e) VL-CDR2 having the amino acid sequence of SEQ ID NO: 93; or (f) VL-CDR3 having the amino acid sequence of SEQ ID NO: 94. In a further aspect, the ActRII binding protein has at least one characteristic selected from the group consisting of: (a) competing with an ActRII ligand (e.g., activin A, activin B, GDF1, GDF3, GDF8 (myostatin), GDF11, BMP6, BMP7, BMP9, or BMP10) for binding to ActRIIB and / or ActRIIA; (b) reducing phosphorylation of Smads (e.g., Smad2 and / or Smad3) in cells expressing ActRIIB and / or ActRIIA in the presence of an ActRIIB and / or ActRIIA ligand (e.g., activin A or GDF8); (c) reducing phosphorylation of ALK4 and / or ALK7 in cells expressing ActRIIB and / or ActRIIA and ALK4 and / or ALK7 in the presence of an ActRIIB and / or ActRIIA ligand; and (d) a K of ≦1 nM and ≧1 pM. D(e.g., as determined by BIACORE® analysis) binds to ActRIIB and / or ActRIIA. In some embodiments, the ActRIIB and / or ActRIIA binding protein has two, three, or four of the above characteristics. In some embodiments, the ActRIIB and / or ActRIIA binding protein has at least two or at least three of the above characteristics.

[0157] In a further aspect, the ActRII binding protein specifically binds to ActRIIB and ActRIIA and comprises a CDR set: VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2, and VL-CDR3, wherein the CDR set comprises: (a) VH-CDR1 having the amino acid sequence of SEQ ID NO: 85, 99, 106, or 113; (b) VH-CDR2 having the amino acid sequence of SEQ ID NO: 86, 100, 107, 114, or 120; (c) VH-CDR3 having the amino acid sequence of SEQ ID NO: 87, 101, 108, 115, or 121; (d) VL-CDR1 having the amino acid sequence of SEQ ID NO: 92; (e) VL-CDR2 having the amino acid sequence of SEQ ID NO: 93; or (f) VL-CDR3 having the amino acid sequence of SEQ ID NO: 94. In a further aspect, the ActRII binding protein has at least one characteristic selected from the group consisting of: (a) competing with an ActRII ligand (e.g., activin A, activin B, GDF1, GDF3, GDF8 (myostatin), GDF11, BMP6, BMP7, BMP9, or BMP10) for binding to ActRIIB and / or ActRIIA; (b) reducing phosphorylation of Smads (e.g., Smad2 and / or Smad3) in cells expressing ActRIIB and / or ActRIIA in the presence of an ActRIIB and / or ActRIIA ligand (e.g., activin A or GDF8); (c) reducing phosphorylation of ALK4 and / or ALK7 in cells expressing ActRIIB and / or ActRIIA and ALK4 and / or ALK7 in the presence of an ActRIIB and / or ActRIIA ligand; and (d) a K of ≦1 nM and ≧1 pM.D (e.g., as determined by BIACORE® analysis) binds to ActRIIB and / or ActRIIA. In some embodiments, the ActRIIB and / or ActRIIA binding protein has two, three, or four of the above characteristics. In some embodiments, the ActRIIB and / or ActRIIA binding protein has at least two or at least three of the above characteristics.

[0158] In a further aspect, the ActRII binding protein specifically binds to ActRIIA and comprises a CDR set: VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2, and VL-CDR3, wherein the CDR set is identical to the reference set of CDRs or has a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or less than 10 amino acid substitutions, deletions, and / or insertions from the reference set of CDRs. The reference set of CDRs has (a) VH-CDR1 having the amino acid sequence of SEQ ID NO: 126; (b) VH-CDR2 having the amino acid sequence of SEQ ID NO: 127; (c) VH-CDR3 having the amino acid sequence of SEQ ID NO: 128; (d) VL-CDR1 having the amino acid sequence of SEQ ID NO: 133; (e) VL-CDR2 having the amino acid sequence of SEQ ID NO: 134; or (f) VL-CDR3 having the amino acid sequence of SEQ ID NO: 135. In a further aspect, the ActRIIA binding protein has at least one characteristic selected from the group consisting of: (a) competing with an ActRIIA ligand (e.g., activin A, activin B, GDF1, GDF3, or Nodal); (b) reducing phosphorylation of Smads (e.g., Smad2 and / or Smad3) in cells expressing ActRIIA in the presence of an ActRIIA ligand (e.g., activin A); (c) reducing phosphorylation of ALK4 and / or ALK7 in cells expressing ActRIIA and ALK4 and / or ALK7 in the presence of an ActRIIA ligand; and (d) a K of ≦1 nM and ≧1 pM. D(e.g., as determined by BIACORE® analysis) binds to ActRIIA. In some embodiments, the ActRIIA binding protein has two, three, or four of the above characteristics. In some embodiments, the ActRIIA binding protein has at least two or at least three of the above characteristics.

[0159] In a further aspect, the ActRII binding protein specifically binds to ActRIIA and comprises a CDR set: VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2, and VL-CDR3, wherein the CDR set is (a) VH-CDR1 having the amino acid sequence of SEQ ID NO: 126; (b) VH-CDR2 having the amino acid sequence of SEQ ID NO: 127; (c) VH-CDR3 having the amino acid sequence of SEQ ID NO: 128; (d) VL-CDR1 having the amino acid sequence of SEQ ID NO: 133; (e) VL-CDR2 having the amino acid sequence of SEQ ID NO: 134; or (f) VL-CDR3 having the amino acid sequence of SEQ ID NO: 135. In a further aspect, the ActRIIA binding protein has at least one characteristic selected from the group consisting of: (a) competing with an ActRIIA ligand (e.g., activin A, activin B, GDF1, GDF3, or Nodal); (b) reducing phosphorylation of Smads (e.g., Smad2 and / or Smad3) in cells expressing ActRIIA in the presence of an ActRIIA ligand (e.g., activin A); (c) reducing phosphorylation of ALK4 and / or ALK7 in cells expressing ActRIIA and ALK4 and / or ALK7 in the presence of an ActRIIA ligand; and (d) a K of ≦1 nM and ≧1 pM. D (e.g., as determined by BIACORE® analysis) binds to ActRIIA. In some embodiments, the ActRIIA binding protein has two, three, or four of the above characteristics. In some embodiments, the ActRIIA binding protein has at least two or at least three of the above characteristics.

[0160] In some aspects, the ActRII binding protein specifically binds ActRII and comprises a set of CDRs, the set of CDRs comprising: (a) (i) VH-CDR1 has the amino acid sequence of SEQ ID NO: 3, 17, 23, 29, 35, or 41; (ii) VH-CDR2 has the amino acid sequence of SEQ ID NO: 4, 18, 24, 30, or 36; (iii) VH-CDR3 has the amino acid sequence of SEQ ID NO: 5; (iv) VL-CDR1 has the amino acid sequence of SEQ ID NO: 10; (v) VL-CDR2 has the amino acid sequence of SEQ ID NO: 11; and (vi (b) (i) VH-CDR1 has the amino acid sequence of SEQ ID NO: 64 or 78; (ii) VH-CDR2 has the amino acid sequence of SEQ ID NO: 65 or 79; (iii) VH-CDR3 has the amino acid sequence of SEQ ID NO: 66 or 80; (iv) VL-CDR1 has the amino acid sequence of SEQ ID NO: 71; (v) VL-CDR2 has the amino acid sequence of SEQ ID NO: 72; and (vi) VL-CDR3 has the amino acid sequence of SEQ ID NO: 73; (c) (i) VH-CDR1 has the amino acid sequence of SEQ ID NO: 3 or 58; (ii) VH-CDR2 has the amino acid sequence of SEQ ID NO: 4 or 59; (iii) VH-CDR3 has the amino acid sequence of SEQ ID NO: 46; (iv) VL-CDR1 has the amino acid sequence of SEQ ID NO: 51; (v) VL-CDR2 has the amino acid sequence of SEQ ID NO: 52; and (vi) VL-CDR3 has the amino acid sequence of SEQ ID NO: 53; the protein binds to ActRIIB; (d) (i) VH-CDR1 has the amino acid sequence of SEQ ID NO: (ii) VH-CDR2 has the amino acid sequence of SEQ ID NO: 86, 100, 107, 114, or 120; (iii) VH-CDR3 has the amino acid sequence of SEQ ID NO: 87, 101, 108, 115, or 121; (iv) VL-CDR1 has the amino acid sequence of SEQ ID NO: 92; (v) VL-CDR2 has the amino acid sequence of SEQ ID NO: 93; and (vi) VL-CDR3 has the amino acid sequence of SEQ ID NO: 94; the protein binds to ActRIIB and ActRIIA;or (e) (i) VH-CDR1 has the amino acid sequence of SEQ ID NO: 126; (ii) VH-CDR2 has the amino acid sequence of SEQ ID NO: 127; (iii) VH-CDR3 has the amino acid sequence of SEQ ID NO: 128; (iv) VL-CDR1 has the amino acid sequence of SEQ ID NO: 133; (v) VL-CDR2 has the amino acid sequence of SEQ ID NO: 134; and (vi) VL-CDR3 has the amino acid sequence of SEQ ID NO: 135; and the protein binds to ActRIIA.

[0161] In a further aspect, the ActRII binding protein comprises a set of CDRs, wherein the set of CDRs is (a) (i) VH-CDR1 has the amino acid sequence of SEQ ID NO: 3; (ii) VH-CDR2 has the amino acid sequence of SEQ ID NO: 4; (iii) VH-CDR3 has the amino acid sequence of SEQ ID NO: 5; (iv) VL-CDR1 has the amino acid sequence of SEQ ID NO: 10; (v) VL-CDR2 has the amino acid sequence of SEQ ID NO: 11; and (vi) VL-CDR3 has the amino acid sequence of SEQ ID NO: 12; wherein the protein binds to ActRIIB; and (b) (i) V (ii) VH-CDR1 has the amino acid sequence of SEQ ID NO: 17; (ii) VH-CDR2 has the amino acid sequence of SEQ ID NO: 18; (iii) VH-CDR3 has the amino acid sequence of SEQ ID NO: 5; (iv) VL-CDR1 has the amino acid sequence of SEQ ID NO: 10; (v) VL-CDR2 has the amino acid sequence of SEQ ID NO: 11; and (vi) VL-CDR3 has the amino acid sequence of SEQ ID NO: 12; the protein binds to ActRIIB; (c)(i) VH-CDR1 has the amino acid sequence of SEQ ID NO: 23; (ii) VH-CDR2 has the amino acid sequence of SEQ ID NO: 24 (iii) VH-CDR3 has the amino acid sequence of SEQ ID NO:5; (iv) VL-CDR1 has the amino acid sequence of SEQ ID NO:10; (v) VL-CDR2 has the amino acid sequence of SEQ ID NO:11; and (vi) VL-CDR3 has the amino acid sequence of SEQ ID NO:12; the protein binds to ActRIIB; (d) (i) VH-CDR1 has the amino acid sequence of SEQ ID NO:29; (ii) VH-CDR2 has the amino acid sequence of SEQ ID NO:30; (iii) VH-CDR3 has the amino acid sequence of SEQ ID NO:5; (iv) VL-CDR1 (v) VL-CDR2 has the amino acid sequence of SEQ ID NO: 11; and (vi) VL-CDR3 has the amino acid sequence of SEQ ID NO: 12; the protein binds to ActRIIB; (e) (i) VH-CDR1 has the amino acid sequence of SEQ ID NO: 35; (ii) VH-CDR2 has the amino acid sequence of SEQ ID NO: 36; (iii) VH-CDR3 has the amino acid sequence of SEQ ID NO: 5; (iv) VL-CDR1 has the amino acid sequence of SEQ ID NO: 10; (v) VL-CDR2 has the amino acid sequence of SEQ ID NO: 11;and (vi) VL-CDR3 has the amino acid sequence of SEQ ID NO: 12; the protein binds to ActRIIB; (f) (i) VH-CDR1 has the amino acid sequence of SEQ ID NO: 41; (ii) VH-CDR2 has the amino acid sequence of SEQ ID NO: 18; (iii) VH-CDR3 has the amino acid sequence of SEQ ID NO: 5; (iv) VL-CDR1 has the amino acid sequence of SEQ ID NO: 10; (v) VL-CDR2 has the amino acid sequence of SEQ ID NO: 11; and (vi) VL-CDR3 has the amino acid sequence of SEQ ID NO: 12; the protein binds to ActRIIB; (g) (i) VH-CDR1 has the amino acid sequence of SEQ ID NO: 64; (ii) VH-CDR2 has the amino acid sequence of SEQ ID NO: 65; (iii) VH-CDR3 has the amino acid sequence of SEQ ID NO: 66; (iv) VL-CDR1 has the amino acid sequence of SEQ ID NO: 71; (v) VL-CDR2 has the amino acid sequence of SEQ ID NO: 72; and (vi) VL-CDR3 has the amino acid sequence of SEQ ID NO: 73; the protein binds to ActRIIB; and (h) (i) VH-CDR1 has the amino acid sequence of SEQ ID NO: 78; (i) VH-CDR2 has the amino acid sequence of SEQ ID NO: 79; (iii) VH-CDR3 has the amino acid sequence of SEQ ID NO: 80; (iv) VL-CDR1 has the amino acid sequence of SEQ ID NO: 71; (v) VL-CDR2 has the amino acid sequence of SEQ ID NO: 72; and (vi) VL-CDR3 has the amino acid sequence of SEQ ID NO: 73; the protein binds to ActRIIB; (i) VH-CDR1 has the amino acid sequence of SEQ ID NO: 3; (ii) VH-CDR2 has the amino acid sequence of SEQ ID NO: 4; and (iii) VH-CDR3 has the amino acid sequence of SEQ ID NO: (iv) VL-CDR1 has the amino acid sequence of SEQ ID NO: 51; (v) VL-CDR2 has the amino acid sequence of SEQ ID NO: 52; and (vi) VL-CDR3 has the amino acid sequence of SEQ ID NO: 53; the protein binds to ActRIIB; (j) (i) VH-CDR1 has the amino acid sequence of SEQ ID NO: 58; (ii) VH-CDR2 has the amino acid sequence of SEQ ID NO: 59; (iii) VH-CDR3 has the amino acid sequence of SEQ ID NO: 46; (iv) VL-CDR1 has the amino acid sequence of SEQ ID NO: 51;(v) VL-CDR2 has the amino acid sequence of SEQ ID NO: 52; and (vi) VL-CDR3 has the amino acid sequence of SEQ ID NO: 53; the protein binds to ActRIIB; (k) (i) VH-CDR1 has the amino acid sequence of SEQ ID NO: 85; (ii) VH-CDR2 has the amino acid sequence of SEQ ID NO: 86; (iii) VH-CDR3 has the amino acid sequence of SEQ ID NO: 87; (iv) VL-CDR1 has the amino acid sequence of SEQ ID NO: 92; (v) VL-CDR2 has the amino acid sequence of SEQ ID NO: 93; and (vi) VL-CDR R3 has the amino acid sequence of SEQ ID NO: 94; the protein binds to ActRIIB and ActRIIA; (l) (i) VH-CDR1 has the amino acid sequence of SEQ ID NO: 99; (ii) VH-CDR2 has the amino acid sequence of SEQ ID NO: 100; (iii) VH-CDR3 has the amino acid sequence of SEQ ID NO: 101; (iv) VL-CDR1 has the amino acid sequence of SEQ ID NO: 92; (v) VL-CDR2 has the amino acid sequence of SEQ ID NO: 93; and (vi) VL-CDR3 has the amino acid sequence of SEQ ID NO: 94; the protein binds to A (m) (i) VH-CDR1 has the amino acid sequence of SEQ ID NO: 106; (ii) VH-CDR2 has the amino acid sequence of SEQ ID NO: 107, (iii) VH-CDR3 has the amino acid sequence of SEQ ID NO: 108; (iv) VL-CDR1 has the amino acid sequence of SEQ ID NO: 92; (v) VL-CDR2 has the amino acid sequence of SEQ ID NO: 93; and (vi) VL-CDR3 has the amino acid sequence of SEQ ID NO: 94; the protein binds ActRIIB and ActRIIA; (n) (i) VH -CDR1 has the amino acid sequence of SEQ ID NO: 113; (ii) VH-CDR2 has the amino acid sequence of SEQ ID NO: 114; (iii) VH-CDR3 has the amino acid sequence of SEQ ID NO: 115; (iv) VL-CDR1 has the amino acid sequence of SEQ ID NO: 92; (v) VL-CDR2 has the amino acid sequence of SEQ ID NO: 93; and (vi) VL-CDR3 has the amino acid sequence of SEQ ID NO: 94; the protein binds to ActRIIB and ActRIIA; or (o)(i) VH-CDR1 has the amino acid sequence of SEQ ID NO: 113;(ii) VH-CDR2 has the amino acid sequence of SEQ ID NO: 120; (iii) VH-CDR3 has the amino acid sequence of SEQ ID NO: 121; (iv) VL-CDR1 has the amino acid sequence of SEQ ID NO: 92; (v) VL-CDR2 has the amino acid sequence of SEQ ID NO: 93; and (vi) VL-CDR3 has the amino acid sequence of SEQ ID NO: 94; the protein binds to ActRIIB and ActRIIA.

[0162] In some embodiments, the ActRII binding protein comprises a VH-CDR3 or VL-CDR3 sequence disclosed herein. In further embodiments, the ActRII binding protein comprises a VH-CDR3 or VL-CDR3 sequence disclosed in Table 1. In some embodiments, the ActRII binding protein comprises a VH-CDR3 and VL-CDR3 sequence disclosed herein. In further embodiments, the ActRII binding protein comprises a VH-CDR3 and VL-CDR3 sequence disclosed in Table 1.

[0163] In a further aspect, the disclosure provides an ActRIIB binding protein comprising a VH-CDR3 having the amino acid sequence of SEQ ID NO: 5, 46, 66, or 80. In some aspects, an ActRIIB binding protein comprises a VH-CDR3 having the amino acid sequence of SEQ ID NO: 5. In a further aspect, an ActRIIB binding protein comprises a VH-CDR3 having the amino acid sequence of SEQ ID NO: 5, and a VH-CDR2 having the amino acid sequence of SEQ ID NO: 4, 18, 24, 30, or 36. In a further aspect, an ActRIIB binding protein comprises a VH-CDR3 having the amino acid sequence of SEQ ID NO: 5, a VH-CDR2 having the amino acid sequence of SEQ ID NO: 4, 18, 24, 30, or 36, and a VH-CDR1 having the amino acid sequence of SEQ ID NO: 3, 17, 23, 29, 35, or 41. In some aspects, an ActRIIB binding protein comprises a VH-CDR3 having the amino acid sequence of SEQ ID NO: 46. In a further aspect, an ActRIIB binding protein comprises a VH-CDR3 having the amino acid sequence of SEQ ID NO: 46, and a VH-CDR2 having the amino acid sequence of SEQ ID NO: 4 or 59. In a further aspect, an ActRIIB binding protein comprises a VH-CDR3 having the amino acid sequence of SEQ ID NO: 46, a VH-CDR2 having the amino acid sequence of SEQ ID NO: 4 or 59, and a VH-CDR1 having the amino acid sequence of SEQ ID NO: 3 or 58. In some aspects, an ActRIIB binding protein comprises a VH-CDR3 having the amino acid sequence of SEQ ID NO: 66. In a further aspect, an ActRIIB binding protein comprises a VH-CDR3 having the amino acid sequence of SEQ ID NO: 66, and a VH-CDR2 having the amino acid sequence of SEQ ID NO: 65. In a further aspect, an ActRIIB binding protein comprises a VH-CDR3 having the amino acid sequence of SEQ ID NO: 66, a VH-CDR2 having the amino acid sequence of SEQ ID NO: 65, and a VH-CDR1 having the amino acid sequence of SEQ ID NO: 64. In some aspects, the ActRIIB binding protein comprises a VH-CDR3 having the amino acid sequence of SEQ ID NO: 80. In further aspects, the ActRIIB binding protein comprises a VH-CDR3 having the amino acid sequence of SEQ ID NO: 80 and a VH-CDR2 having the amino acid sequence of SEQ ID NO: 79.In a further aspect, the ActRIIB binding protein comprises a VH-CDR3 having the amino acid sequence of SEQ ID NO: 80, a VH-CDR2 having the amino acid sequence of SEQ ID NO: 79, and a VH-CDR1 having the amino acid sequence of SEQ ID NO: 78. In a further aspect, the ActRIIB binding protein has at least one characteristic selected from the group consisting of: (a) competes with an ActRII ligand (e.g., activin A, activin B, GDF1, GDF3, GDF8 (myostatin), GDF11, BMP6, BMP7, BMP9, or BMP10) for binding to ActRIIB; (b) reduces phosphorylation of Smads (e.g., Smad2 and / or Smad3) in cells expressing ActRIIB in the presence of an ActRIIB ligand (e.g., activin A or GDF8); (c) reduces phosphorylation of ALK4 and / or ALK7 in cells expressing ActRIIB and ALK4 and / or ALK7 in the presence of an ActRIIB ligand; and (d) a K of ≦1 nM and ≧1 pM. D (e.g., as determined by BIACORE® analysis) binds to ActRIIB. In some embodiments, the ActRIIB-binding protein has two, three, or four of the above characteristics. In some embodiments, the ActRIIB-binding protein has at least two or at least three of the above characteristics.

[0164] In a further aspect, the disclosure provides an ActRIIB binding protein comprising a VL-CDR3 having the amino acid sequence of SEQ ID NO: 12, 53, or 73. In some aspects, the ActRIIB binding protein comprises a VL-CDR3 having the amino acid sequence of SEQ ID NO: 12. In a further aspect, the ActRIIB binding protein comprises a VL-CDR3 having the amino acid sequence of SEQ ID NO: 12, and a VL-CDR2 having the amino acid sequence of SEQ ID NO: 11. In a further aspect, the ActRIIB binding protein comprises a VL-CDR3 having the amino acid sequence of SEQ ID NO: 12, a VL-CDR2 having the amino acid sequence of SEQ ID NO: 11, and a VL-CDR1 having the amino acid sequence of SEQ ID NO: 10. In some aspects, the ActRIIB binding protein comprises a VL-CDR3 having the amino acid sequence of SEQ ID NO: 53. In a further aspect, the ActRIIB binding protein comprises a VL-CDR3 having the amino acid sequence of SEQ ID NO: 53, and a VL-CDR2 having the amino acid sequence of SEQ ID NO: 52. In further aspects, the ActRIIB binding protein comprises a VL-CDR3 having the amino acid sequence of SEQ ID NO: 53, a VL-CDR2 having the amino acid sequence of SEQ ID NO: 52, and a VL-CDR1 having the amino acid sequence of SEQ ID NO: 51. In some aspects, the ActRIIB binding protein comprises a VL-CDR3 having the amino acid sequence of SEQ ID NO: 73. In further aspects, the ActRIIB binding protein comprises a VL-CDR3 having the amino acid sequence of SEQ ID NO: 73, and a VL-CDR2 having the amino acid sequence of SEQ ID NO: 72. In still further aspects, the ActRIIB binding protein comprises a VL-CDR3 having the amino acid sequence of SEQ ID NO: 73, a VL-CDR2 having the amino acid sequence of SEQ ID NO: 72, and a VL-CDR1 having the amino acid sequence of SEQ ID NO: 71.In a further aspect, the ActRIIB binding protein has at least one characteristic selected from the group consisting of: (a) competes with an ActRII ligand (e.g., activin A, activin B, GDF1, GDF3, GDF8 (myostatin), GDF11, BMP6, BMP7, BMP9, or BMP10) for binding to ActRIIB; (b) reduces phosphorylation of Smads (e.g., Smad2 and / or Smad3) in cells expressing ActRIIB in the presence of an ActRIIB ligand (e.g., activin A or GDF8); (c) reduces phosphorylation of ALK4 and / or ALK7 in cells expressing ActRIIB and ALK4 and / or ALK7 in the presence of an ActRIIB ligand; and (d) a K of ≦1 nM and ≧1 pM. D (e.g., as determined by BIACORE® analysis) binds to ActRIIB. In some embodiments, the ActRIIB-binding protein has two, three, or four of the above characteristics. In some embodiments, the ActRIIB-binding protein has at least two or at least three of the above characteristics.

[0165] In a further aspect, the disclosure provides an ActRIIB and / or ActRIIA binding protein comprising a VH-CDR3 having the amino acid sequence of SEQ ID NO: 87, 101, 108, 115, or 121. In a further aspect, the ActRII binding protein comprises a VH-CDR3 having the amino acid sequence of SEQ ID NO: 87, 101, 108, 115, or 121, and a VH-CDR2 having the amino acid sequence of SEQ ID NO: 86, 100, 107, 114, or 120. In a further aspect, the ActRII binding protein comprises a VH-CDR3 having the amino acid sequence of SEQ ID NO: 87, 101, 108, 115, or 121, a VH-CDR2 having the amino acid sequence of SEQ ID NO: 86, 100, 107, 114, or 120, and a VH-CDR1 having the amino acid sequence of SEQ ID NO: 85, 99, 106, or 113. In some aspects, an ActRIIB and / or ActRIIA binding protein comprises a VH-CDR3 having the amino acid sequence of SEQ ID NO: 87. In a further aspect, an ActRIIB and / or ActRIIA binding protein comprises a VH-CDR3 having the amino acid sequence of SEQ ID NO: 87, and a VH-CDR2 having the amino acid sequence of SEQ ID NO: 86. In a further aspect, an ActRIIB and / or ActRIIA binding protein comprises a VH-CDR3 having the amino acid sequence of SEQ ID NO: 87, a VH-CDR2 having the amino acid sequence of SEQ ID NO: 86, and a VH-CDR1 having the amino acid sequence of SEQ ID NO: 85. In some aspects, an ActRIIB and / or ActRIIA binding protein comprises a VH-CDR3 having the amino acid sequence of SEQ ID NO: 101. In a further aspect, an ActRIIB and / or ActRIIA binding protein comprises a VH-CDR3 having the amino acid sequence of SEQ ID NO: 101, and a VH-CDR2 having the amino acid sequence of SEQ ID NO: 100. In further aspects, the ActRIIB and / or ActRIIA binding protein comprises a VH-CDR3 having the amino acid sequence of SEQ ID NO: 101, a VH-CDR2 having the amino acid sequence of SEQ ID NO: 100, and a VH-CDR1 having the amino acid sequence of SEQ ID NO: 99. In some aspects, the ActRIIB and / or ActRIIA binding protein comprises a VH-CDR3 having the amino acid sequence of SEQ ID NO: 108.In further aspects, the ActRIIB and / or ActRIIA binding protein comprises a VH-CDR3 having the amino acid sequence of SEQ ID NO: 108, and a VH-CDR2 having the amino acid sequence of SEQ ID NO: 107. In further aspects, the ActRIIB and / or ActRIIA binding protein comprises a VH-CDR3 having the amino acid sequence of SEQ ID NO: 108, a VH-CDR2 having the amino acid sequence of SEQ ID NO: 107, and a VH-CDR1 having the amino acid sequence of SEQ ID NO: 106. In some aspects, the ActRIIB and / or ActRIIA binding protein comprises a VH-CDR3 having the amino acid sequence of SEQ ID NO: 115. In further aspects, the ActRIIB and / or ActRIIA binding protein comprises a VH-CDR3 having the amino acid sequence of SEQ ID NO: 115, and a VH-CDR2 having the amino acid sequence of SEQ ID NO: 114. In a further aspect, the ActRIIB and / or ActRIIA binding protein comprises a VH-CDR3 having the amino acid sequence of SEQ ID NO: 115, a VH-CDR2 having the amino acid sequence of SEQ ID NO: 114, and a VH-CDR1 having the amino acid sequence of SEQ ID NO: 113. In a further aspect, the ActRIIB and / or ActRIIA binding protein comprises a VH-CDR3 having the amino acid sequence of SEQ ID NO: 121, a VH-CDR2 having the amino acid sequence of SEQ ID NO: 120, and a VH-CDR1 having the amino acid sequence of SEQ ID NO: 113.In a further aspect, the ActRII binding protein has at least one characteristic selected from the group consisting of: (a) competing with an ActRII ligand (e.g., activin A, activin B, GDF1, GDF3, GDF8 (myostatin), GDF11, BMP6, BMP7, BMP9, or BMP10) for binding to ActRIIB and / or ActRIIA; (b) reducing phosphorylation of Smads (e.g., Smad2 and / or Smad3) in cells expressing ActRIIB and / or ActRIIA in the presence of an ActRIIB and / or ActRIIA ligand (e.g., activin A or GDF8); (c) reducing phosphorylation of ALK4 and / or ALK7 in cells expressing ActRIIB and / or ActRIIA and ALK4 and / or ALK7 in the presence of an ActRIIB and / or ActRIIA ligand; and (d) a K of ≦1 nM and ≧1 pM. D (e.g., as determined by BIACORE® analysis) binds to ActRIIB and / or ActRIIA. In some embodiments, the ActRIIB and / or ActRIIA binding protein has two, three, or four of the above characteristics. In some embodiments, the ActRIIB and / or ActRIIA binding protein has at least two or at least three of the above characteristics.

[0166] In a further aspect, the disclosure provides an ActRIIB and / or ActRIIA binding protein comprising a VL-CDR3 having the amino acid sequence of SEQ ID NO: 94. In some aspects, the ActRIIB and / or ActRIIA binding protein comprises a VL-CDR3 having the amino acid sequence of SEQ ID NO: 94, and a VL-CDR2 having the amino acid sequence of SEQ ID NO: 93. In a further aspect, the ActRIIB binding protein comprises a VL-CDR3 having the amino acid sequence of SEQ ID NO: 94, a VL-CDR2 having the amino acid sequence of SEQ ID NO: 93, and a VL-CDR1 having the amino acid sequence of SEQ ID NO: 92. In a further aspect, the ActRII binding protein has at least one characteristic selected from the group consisting of: (a) competing with an ActRII ligand (e.g., activin A, activin B, GDF1, GDF3, GDF8 (myostatin), GDF11, BMP6, BMP7, BMP9, or BMP10) for binding to ActRIIB and / or ActRIIA; (b) reducing phosphorylation of Smads (e.g., Smad2 and / or Smad3) in cells expressing ActRIIB and / or ActRIIA in the presence of an ActRIIB and / or ActRIIA ligand (e.g., activin A or GDF8); (c) reducing phosphorylation of ALK4 and / or ALK7 in cells expressing ActRIIB and / or ActRIIA and ALK4 and / or ALK7 in the presence of an ActRIIB and / or ActRIIA ligand; and (d) a K of ≦1 nM and ≧1 pM. D (e.g., as determined by BIACORE® analysis) binds to ActRIIB and / or ActRIIA. In some embodiments, the ActRIIB and / or ActRIIA binding protein has two, three, or four of the above characteristics. In some embodiments, the ActRIIB and / or ActRIIA binding protein has at least two or at least three of the above characteristics.

[0167] In a further aspect, the disclosure provides an ActRIIB and / or ActRIIA binding protein comprising a VH-antigen binding domain 3 (ABD3) having the amino acid sequence of SEQ ID NO: 142. In a further aspect, the ActRII binding protein comprises a VH-ABD3 having the amino acid sequence of SEQ ID NO: 142, and a VH-antigen binding domain 2 (VH-ABD2) having the amino acid sequence of SEQ ID NO: 141. In a further aspect, the ActRII binding protein comprises a VH-ABD3 having the amino acid sequence of SEQ ID NO: 133, a VH-ABD2 having the amino acid sequence of SEQ ID NO: 141, and a VH-antigen binding domain 1 (VH-ABD1) having the amino acid sequence of SEQ ID NO: 140. In a further aspect, the ActRIIB and ActRIIA binding proteins have at least one characteristic selected from the group consisting of: (a) compete with an ActRII ligand (e.g., activin A, activin B, GDF1, GDF3, GDF8 (myostatin), GDF11, BMP6, BMP7, BMP9, or BMP10) for binding to ActRIIB or ActRIIA; (b) decrease phosphorylation of Smads (e.g., Smad2 and / or Smad3) in cells expressing ActRIIB and / or ActRIIA in the presence of an ActRIIB and / or ActRIIA ligand (e.g., activin A); (c) decrease phosphorylation of ALK4 and / or ALK7 in cells expressing ActRIIB and / or ActRIIA and ALK4 and / or ALK7 in the presence of an ActRIIB and / or ActRIIA ligand; and (d) a K of ≦1 nM and ≧1 pM. D (e.g., as determined by BIACORE® analysis) binds to ActRIIB and / or ActRIIA. In some embodiments, the ActRIIB and ActRIIA binding proteins have two, three, or four of the above characteristics. In some embodiments, the ActRIIB and ActRIIA binding proteins have at least two or at least three of the above characteristics.

[0168] In a further aspect, the disclosure provides an ActRIIA binding protein comprising a VH-CDR3 having the amino acid sequence of SEQ ID NO: 128. In a further aspect, the ActRII binding protein comprises a VH-CDR3 having the amino acid sequence of SEQ ID NO: 128, and a VH-CDR2 having the amino acid sequence of SEQ ID NO: 127. In a further aspect, the ActRII binding protein comprises a VH-CDR3 having the amino acid sequence of SEQ ID NO: 128, a VH-CDR2 having the amino acid sequence of SEQ ID NO: 127, and a VH-CDR1 having the amino acid sequence of SEQ ID NO: 126. In a further aspect, the ActRIIA binding protein has at least one characteristic selected from the group consisting of: (a) competing with an ActRIIA ligand (e.g., activin A, activin B, GDF1, GDF3, or Nodal); (b) reducing phosphorylation of Smads (e.g., Smad2 and / or Smad3) in cells expressing ActRIIA in the presence of an ActRIIA ligand (e.g., activin A); (c) reducing phosphorylation of ALK4 and / or ALK7 in cells expressing ActRIIA and ALK4 and / or ALK7 in the presence of an ActRIIA ligand; and (d) a K of ≦1 nM and ≧1 pM. D (e.g., as determined by BIACORE® analysis) binds to ActRIIA. In some embodiments, the ActRIIA binding protein has two, three, or four of the above characteristics. In some embodiments, the ActRIIA binding protein has at least two or at least three of the above characteristics.

[0169] In a further aspect, the disclosure provides an ActRIIA binding protein comprising a VL-CDR3 having the amino acid sequence of SEQ ID NO: 135. In a further aspect, the ActRII binding protein comprises a VL-CDR3 having the amino acid sequence of SEQ ID NO: 135, and a VL-CDR2 having the amino acid sequence of SEQ ID NO: 134. In a further aspect, the ActRII binding protein comprises a VL-CDR3 having the amino acid sequence of SEQ ID NO: 135, a VL-CDR2 having the amino acid sequence of SEQ ID NO: 134, and a VL-CDR1 having the amino acid sequence of SEQ ID NO: 133. In a further aspect, the ActRIIA binding protein has at least one characteristic selected from the group consisting of: (a) competing with an ActRIIA ligand (e.g., activin A, activin B, GDF1, GDF3, or Nodal); (b) reducing phosphorylation of Smads (e.g., Smad2 and / or Smad3) in cells expressing ActRIIA in the presence of an ActRIIA ligand (e.g., activin A); (c) reducing phosphorylation of ALK4 and / or ALK7 in cells expressing ActRIIA and ALK4 and / or ALK7 in the presence of an ActRIIA ligand; and (d) a K of ≦1 nM and ≧1 pM. D (e.g., as determined by BIACORE® analysis) binds to ActRIIA. In some embodiments, the ActRIIA binding protein has two, three, or four of the above characteristics. In some embodiments, the ActRIIA binding protein has at least two or at least three of the above characteristics.

[0170] In some aspects, an ActRII binding protein comprises a VH or VL that has a total of less than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, or 0 amino acid substitutions, deletions, and / or insertions compared to a reference VH or VL disclosed herein. In further aspects, an ActRII binding protein comprises a VH or VL that has a total of less than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, or 0 amino acid substitutions, deletions, and / or insertions compared to a reference VH or VL disclosed in Table 1. In some aspects, an ActRII binding protein comprises a VH and VL pair that has a total of less than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, or 0 amino acid substitutions, deletions, and / or insertions compared to a reference VH and VL pair disclosed herein. In a further aspect, the ActRII binding protein comprises a VH and VL pair having a total of less than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, or 0 amino acid substitutions, deletions, and / or insertions compared to a reference VH and VL pair disclosed in Table 1.

[0171] In some embodiments, the ActRII binding protein comprises a VH and VL pair selected from the group consisting of: (a) (i) a VH sequence having a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15 or fewer than 0 amino acid substitutions, deletions, and / or insertions from a reference VH sequence selected from the group consisting of SEQ ID NOs: 2, 16, 22, 28, 34, or 40, and (ii) a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15 or fewer than 0 amino acid substitutions, deletions, and / or insertions from a reference VL sequence of SEQ ID NO: 9, or and (b) (i) a VH sequence having a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15 or less than 0 amino acid substitutions, deletions, and / or insertions from a reference VH sequence of SEQ ID NO: 45 or 57, and (ii) a VL sequence having a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15 or less than 0 amino acid substitutions, deletions, and / or insertions from a reference VL sequence of SEQ ID NO: 50. (c)(i) a VH sequence having a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15 or less than 0 amino acid substitutions, deletions, and / or insertions from a reference VH sequence of SEQ ID NO: 63 or 77, and (ii) a VL sequence having a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15 or less than 0 amino acid substitutions, deletions, and / or insertions from a reference VL sequence of SEQ ID NO: 70, the protein binds to ActRIIB; (d)(i) a VH sequence having a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15 or less than 0 amino acid substitutions, deletions, and / or insertions from a reference VH sequence selected from the group consisting of SEQ ID NOs: 84, 98, 105, 112, or 119, and (ii) a VL sequence having a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15 or less than 0 amino acid substitutions, deletions, and / or insertions from a reference VL sequence of SEQ ID NO: 91, wherein the protein binds to ActRIIB and ActRIIA;and (e) (i) a VH sequence having a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15 or less than 0 amino acid substitutions, deletions, and / or insertions from a reference VH sequence of SEQ ID NO: 125, and (ii) a VL sequence having a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15 or less than 0 amino acid substitutions, deletions, and / or insertions from a reference VL sequence of SEQ ID NO: 132, wherein the protein binds to ActRIIA;

[0172] In some aspects, the ActRII binding protein comprises a VH and VL pair having (i) a VH sequence having a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15 or less than 0 amino acid substitutions, deletions, and / or insertions from the reference VH sequence of SEQ ID NO: 144, and (ii) a VL sequence having a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15 or less than 0 amino acid substitutions, deletions, and / or insertions from the reference VL sequence of SEQ ID NO: 151, wherein the protein binds to ActRIIB.

[0173] In some aspects, the ActRII binding protein comprises a VH and VL pair having (i) a VH sequence having a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15 or less than 0 amino acid substitutions, deletions, and / or insertions from the reference VH sequence of SEQ ID NO: 165, and (ii) a VL sequence having a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15 or less than 0 amino acid substitutions, deletions, and / or insertions from the reference VL sequence of SEQ ID NO: 172, wherein the protein binds to ActIIRA and ActRIIB.

[0174] In a further aspect, the ActRII binding protein comprises a VH and VL pair, wherein the VH sequence has a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15 or less, or 0 amino acid substitutions, deletions, and / or insertions from the reference VH sequence of SEQ ID NO: 2; and the VL sequence has a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15 or less, or 0 amino acid substitutions, deletions, and / or insertions from the reference VL sequence of SEQ ID NO: 9; and the protein binds ActRIIB; and (b) the VH sequence has a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15 or less, or 0 amino acid substitutions, deletions, and / or insertions from the reference VH sequence of SEQ ID NO: 16. , 9, 10, 15, or less than 0 amino acid substitutions, deletions, and / or insertions from the reference VL sequence of SEQ ID NO: 9; and the protein binds ActRIIB; (c) the VH sequence has a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, or less than 0 amino acid substitutions, deletions, and / or insertions from the reference VH sequence of SEQ ID NO: 22; and the VL sequence has a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, or less than 0 amino acid substitutions, deletions, and / or insertions from the reference VL sequence of SEQ ID NO: 9. (d) the VH sequence has a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, or less than 0 amino acid substitutions, deletions, and / or insertions from a reference VH sequence of SEQ ID NO: 28; and the VL sequence has a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, or less than 0 amino acid substitutions, deletions, and / or insertions from a reference VL sequence of SEQ ID NO: 9; and the protein binds ActRIIB; (e) the VH sequence (f) the VH sequence has a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15 or less, or 0 amino acid substitutions, deletions, and / or insertions from the reference VH sequence of SEQ ID NO: 34; and the VL sequence has a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15 or less, or 0 amino acid substitutions, deletions, and / or insertions from the reference VL sequence of SEQ ID NO: 9; and the protein binds ActRIIB; (f) the VH sequence has a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15 or less, or 0 amino acid substitutions, deletions, and / or insertions from the reference VH sequence of SEQ ID NO: 40;and the VL sequence has a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15 or less than 0 amino acid substitutions, deletions, and / or insertions from a reference VL sequence of SEQ ID NO: 9; and the protein binds ActRIIB; (g) the sequence has a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15 or less than 0 amino acid substitutions, deletions, and / or insertions from a reference VH sequence of SEQ ID NO: 45; and the VL sequence has a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15 or less than 0 amino acid substitutions, deletions, and / or insertions from a reference VL sequence of SEQ ID NO: 50. and wherein the protein binds ActRIIB; (h) the VH sequence has a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15 or less than 0 amino acid substitutions, deletions, and / or insertions from the reference VH sequence of SEQ ID NO: 57; and the VL sequence has a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15 or less than 0 amino acid substitutions, deletions, and / or insertions from the reference VL sequence of SEQ ID NO: 50; and the protein binds ActRIIB; (i) the VH sequence has a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15 or less than 0 amino acid substitutions, deletions, and / or insertions from the reference VH sequence of SEQ ID NO: 63. and the VL sequence has a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, or 0 amino acid substitutions, deletions, and / or insertions from the reference VL sequence of SEQ ID NO: 70; and the protein binds ActRIIB; (j) the VH sequence has a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, or 0 amino acid substitutions, deletions, and / or insertions from the reference VH sequence of SEQ ID NO: 77; and the VL sequence has a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, or 0 amino acid substitutions, deletions, and / or insertions from the reference VL sequence of SEQ ID NO: 70. , 6, 7, 8, 9, 10, 15, or less than 0 amino acid substitutions, deletions, and / or insertions; and the protein binds ActRIIB; (k) the sequence has a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, or less than 0 amino acid substitutions, deletions, and / or insertions from the reference VH sequence of SEQ ID NO: 84; and the VL sequence has a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, or less than 0 amino acid substitutions, deletions, and / or insertions from the reference VL sequence of SEQ ID NO: 91; and the protein binds ActRIIB and ActRIIA;(l) the VH sequence has a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15 or less, or 0 amino acid substitutions, deletions, and / or insertions from the reference VH sequence of SEQ ID NO: 98; and the VL sequence has a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15 or less, or 0 amino acid substitutions, deletions, and / or insertions from the reference VL sequence of SEQ ID NO: 91; and the protein binds ActRIIB and ActRIIA; (m) the VH sequence has a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15 or less, or 0 amino acid substitutions, deletions, and / or insertions from the reference VH sequence of SEQ ID NO: 105. and the VL sequence has a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, or 0 amino acid substitutions, deletions, and / or insertions from a reference VL sequence of SEQ ID NO: 91; the protein binds ActRIIB and ActRIIA; (n) the VH sequence has a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, or 0 amino acid substitutions, deletions, and / or insertions from a reference VH sequence of SEQ ID NO: 112; and the VL sequence has a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, or 0 amino acid substitutions, deletions, and / or insertions from a reference VH sequence of SEQ ID NO: 112; (o) the VH sequence has a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15 or less than 0 amino acid substitutions, deletions, and / or insertions from the reference VL sequence of SEQ ID NO: 119; and the VL sequence has a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15 or less than 0 amino acid substitutions, deletions, and / or insertions from the reference VL sequence of SEQ ID NO: 91. or (p) the VH sequence has a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15 or less, or 0 amino acid substitutions, deletions, and / or insertions from the reference VH sequence of SEQ ID NO: 125; and the VL sequence has a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15 or less, or 0 amino acid substitutions, deletions, and / or insertions from the reference VL sequence of SEQ ID NO: 132; and the protein binds to ActRIIA;

[0175] In a further aspect, the ActRII binding protein comprises a VH and VL pair, wherein the VH sequence has a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15 or less, or 0 amino acid substitutions, deletions, and / or insertions from the reference VH sequence of SEQ ID NO: 144; and the VL sequence has a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15 or less, or 0 amino acid substitutions, deletions, and / or insertions from the reference VL sequence of SEQ ID NO: 151, and the protein binds to ActRIIB.

[0176] In a further aspect, the ActRII binding protein comprises a VH and VL pair, wherein the VH sequence has a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15 or less, or 0 amino acid substitutions, deletions, and / or insertions from the reference VH sequence of SEQ ID NO: 165; and the VL sequence has a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15 or less, or 0 amino acid substitutions, deletions, and / or insertions from the reference VL sequence of SEQ ID NO: 172, and the protein binds to ActIIRA and ActRIIB.

[0177] In some embodiments, an ActRII binding protein comprises a VH or VL having at least 90%, 95%, 97%, 98%, or 99% sequence identity to a reference VH or VL disclosed herein. In further embodiments, an ActRII binding protein comprises a VH or VL having at least 90%, 95%, 97%, 98%, or 99% sequence identity to a reference VH or VL disclosed in Table 1. In some embodiments, an ActRII binding protein comprises a VH and VL having at least 90%, 95%, 97%, 98%, or 99% sequence identity to a reference VH and VL disclosed herein. In further embodiments, an ActRII binding protein comprises a VH and VL having at least 90%, 95%, 97%, 98%, or 99% sequence identity to a reference VH and VL disclosed in Table 1. In a further aspect, the ActRIIB binding protein has at least one characteristic selected from the group consisting of: (a) competes with an ActRII ligand (e.g., activin A, activin B, GDF1, GDF3, GDF8 (myostatin), GDF11, BMP6, BMP7, BMP9, or BMP10) for binding to ActRII; (b) reduces phosphorylation of Smads (e.g., Smad2 and / or Smad3) in cells expressing ActRII in the presence of an ActRII ligand (e.g., activin A or GDF8); (c) reduces phosphorylation of ALK4 and / or ALK7 in cells expressing ActRII and ALK4 and / or ALK7 in the presence of an ActRII ligand; and (d) a K of ≦1 nM and ≧1 pM. D (e.g., as determined by BIACORE® analysis) binds to ActRII. In some embodiments, the ActRII binding protein has two, three, or four of the above characteristics. In some embodiments, the ActRII binding protein has at least two or at least three of the above characteristics.

[0178] In some embodiments, the ActRII binding protein specifically binds ActRII and comprises a VH and VL pair selected from the group consisting of: (a) (i) a VH having at least 90%, 95%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 2, 16, 22, 28, 34, or 40, and (ii) a VL having at least 90%, 95%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 9, wherein the protein binds ActRIIB; (b) (i) a VH having at least 90%, 95%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 45 or 57, and (ii) a VL having at least 90%, 95%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 50, wherein the protein binds ActRIIB; (c) (i) a VH having at least 90%, 95%, 97%, 98%, or 99% sequence identity to SEQ ID NO: (d) (i) a VH having an amino acid sequence of SEQ ID NO: 84, 98, 105, 112, or 119, and (ii) a VL having an amino acid sequence of SEQ ID NO: 91, the protein binds to ActRIIB and ActRIIA; and (e) (i) a VH having at least 90%, 95%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 125, and (ii) a VL having at least 90%, 95%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 132, the protein binds to ActRIIA.In a further aspect, the ActRIIB binding protein has at least one characteristic selected from the group consisting of: (a) competes with an ActRII ligand (e.g., activin A, activin B, GDF1, GDF3, GDF8 (myostatin), GDF11, BMP6, BMP7, BMP9, or BMP10) for binding to ActRII; (b) reduces phosphorylation of Smads (e.g., Smad2 and / or Smad3) in cells expressing ActRII in the presence of an ActRII ligand (e.g., activin A or GDF8); (c) reduces phosphorylation of ALK4 and / or ALK7 in cells expressing ActRII and ALK4 and / or ALK7 in the presence of an ActRII ligand; and (d) a K of ≦1 nM and ≧1 pM. D (e.g., as determined by BIACORE® analysis) binds to ActRII. In some embodiments, the ActRII binding protein has two, three, or four of the above characteristics. In some embodiments, the ActRII binding protein has at least two or at least three of the above characteristics.

[0179] In some aspects, the ActRII binding protein binds to ActRIIB and comprises a VH and VL pair selected from (i) a VH having at least 90%, 95%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 144, and (ii) a VL having at least 90%, 95%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 151, wherein the protein binds to ActRIIB. In a further aspect, the ActRIIB binding protein has at least one characteristic selected from the group consisting of: (a) competes with an ActRII ligand (e.g., activin A, activin B, GDF1, GDF3, GDF8 (myostatin), GDF11, BMP6, BMP7, BMP9, or BMP10) for binding to ActRII; (b) reduces phosphorylation of Smads (e.g., Smad2 and / or Smad3) in cells expressing ActRII in the presence of an ActRII ligand (e.g., activin A or GDF8); (c) reduces phosphorylation of ALK4 and / or ALK7 in cells expressing ActRII and ALK4 and / or ALK7 in the presence of an ActRII ligand; and (d) a K of ≦1 nM and ≧1 pM. D (e.g., as determined by BIACORE® analysis) binds to ActRII. In some embodiments, the ActRII binding protein has two, three, or four of the above characteristics. In some embodiments, the ActRII binding protein has at least two or at least three of the above characteristics.

[0180] In some aspects, the ActRII binding protein binds to ActRIIB and comprises (i) a VH having at least 90%, 95%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 165, and (ii) a VL having at least 90%, 95%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 172, wherein the protein binds to ActIIRA and ActRIIB. In a further aspect, the ActRII binding protein has at least one characteristic selected from the group consisting of: (a) competes with an ActRII ligand (e.g., activin A, activin B, GDF1, GDF3, GDF8 (myostatin), GDF11, BMP6, BMP7, BMP9, or BMP10) for binding to ActRII; (b) reduces phosphorylation of Smads (e.g., Smad2 and / or Smad3) in cells expressing ActRII in the presence of an ActRII ligand (e.g., activin A or GDF8); (c) reduces phosphorylation of ALK4 and / or ALK7 in cells expressing ActRII and ALK4 and / or ALK7 in the presence of an ActRII ligand; and (d) a K of ≦1 nM and ≧1 pM. D (e.g., as determined by BIACORE® analysis) binds to ActRII. In some embodiments, the ActRII binding protein has two, three, or four of the above characteristics. In some embodiments, the ActRII binding protein has at least two or at least three of the above characteristics.

[0181] In a further aspect, the ActRII binding protein specifically binds to ActRII, and (a) a VH sequence of SEQ ID NO: 2, 16, 22, 28, 34, or 40 and a VL sequence of SEQ ID NO: 9; the protein binds to ActRIIB; (b) a VH sequence of SEQ ID NO: 45 or 57 and a VL sequence of SEQ ID NO: 50; the protein binds to ActRIIB; (c) a VH sequence of SEQ ID NO: 63 or 77 and a VL sequence of SEQ ID NO: 70; the protein binds to ActRIIB; (d) a VH sequence of SEQ ID NO: 84, 98, 105, 112, or 119 and a VL sequence of SEQ ID NO: 91; the protein binds to ActRIIB; and (e) a VH sequence of SEQ ID NO: 125 and a VL sequence of SEQ ID NO: 132 protein binds to ActRIIA. In a further aspect, the ActRII binding protein comprises a VH and VL pair selected from the group consisting of: (a) a VH sequence of SEQ ID NO: 2 and a VL sequence of SEQ ID NO: 9; (b) a VH sequence of SEQ ID NO: 16 and a VL sequence of SEQ ID NO: 9; (c) a VH sequence of SEQ ID NO: 22 and a VL sequence of SEQ ID NO: 9; (d) a VH sequence of SEQ ID NO: 28 and a VL sequence of SEQ ID NO: 9; (e) a VH sequence of SEQ ID NO: 34 and a VL sequence of SEQ ID NO: 9; (f) a VH sequence of SEQ ID NO: 40 and a VL sequence of SEQ ID NO: 9; (g) a VH sequence of SEQ ID NO: 45 and a VL sequence of SEQ ID NO: 50; (h) a VH sequence of SEQ ID NO: 57 and a VL sequence of SEQ ID NO: (i) the VH sequence of SEQ ID NO: 63 and the VL sequence of SEQ ID NO: 70; (j) the VH sequence of SEQ ID NO: 77 and the VL sequence of SEQ ID NO: 70; (k) the VH sequence of SEQ ID NO: 84 and the VL sequence of SEQ ID NO: 91; (l) the VH sequence of SEQ ID NO: 98 and the VL sequence of SEQ ID NO: 91; (m) the VH sequence of SEQ ID NO: 105 and the VL sequence of SEQ ID NO: 91; (n) the VH sequence of SEQ ID NO: 112 and the VL sequence of SEQ ID NO: 91; (o) the VH sequence of SEQ ID NO: 119 and the VL sequence of SEQ ID NO: 91; and (p) the VH sequence of SEQ ID NO: 125 and the VL sequence of SEQ ID NO: 132.

[0182] In a further aspect, the ActRII binding protein specifically binds ActRII and comprises a VH sequence of SEQ ID NO: 144 and a VL sequence of SEQ ID NO: 151, and the protein binds to ActRIIB.

[0183] In a further aspect, the ActRII binding protein specifically binds ActRII and comprises a VH sequence of SEQ ID NO: 165 and a VL sequence of SEQ ID NO: 172, and the protein binds to ActIIRA and ActRIIB.

[0184] In some embodiments, the ActRII binding protein comprises a VH and VL pair selected from the group consisting of: (a) a VH protein having at least 90%, 95%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 2 and a VL protein having at least 90%, 95%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 9, which binds ActRIIB; (b) a VH protein having at least 90%, 95%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 16, and and a VL protein having at least 90%, 95%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 9, binds ActRIIB; (c) a VH protein having at least 90%, 95%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 22, and a VL protein having at least 90%, 95%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 9, binds ActRIIB; (d) a VH protein having at least 90%, 95%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 28, (e) a VH having at least 90%, 95%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 34 and a VL having at least 90%, 95%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 9, the protein binds ActRIIB; (f) a VH having at least 90%, 95%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 40, the protein binds ActRIIB; (g) a VH having 0%, 95%, 97%, 98%, or 99% sequence identity and a VL having at least 90%, 95%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 9, wherein the protein binds to ActRIIB; (g) a VH having at least 90%, 95%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 45 and a VL having at least 90%, 95%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 50, wherein the protein binds to ActRIIB;(h) a VH having at least 90%, 95%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 57 and a VL having at least 90%, 95%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 50, the protein binds ActRIIB; (i) a VH having at least 90%, 95%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 63 and a VL having at least 90%, 95%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 70. L, the protein binds ActRIIB; (j) a VH having at least 90%, 95%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 77 and a VL having at least 90%, 95%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 70; the protein binds ActRIIB; (k) a VH having at least 90%, 95%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 84 and at least 90%, 95%, 97%, (l) a VL1 having at least 90%, 95%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 98, and a VH having at least 90%, 95%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 91, the protein binds to ActRIIB and ActRIIA; (m) a VL1 having at least 90%, 95%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 105, the protein binds to ActRIIB and ActRIIA; (n) a VH having at least 90%, 95%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 112 and a VL1 having at least 90%, 95%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 91, wherein the protein binds to ActRIIB and ActRIIA;(o) a VH having at least 90%, 95%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 119 and a VL1 having at least 90%, 95%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 91, the protein binds to ActRIIB and ActRIIA; and (p) a VH having at least 90%, 95%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 125 and a VL having at least 90%, 95%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 132, the protein binds to ActRIIA. In further aspects, the ActRIIB binding protein has at least one characteristic selected from the group consisting of: (a) competes with an ActRII ligand (e.g., activin A, activin B, GDF1, GDF3, GDF8 (myostatin), GDF11, BMP6, BMP7, BMP9, or BMP10) for binding to ActRII; (b) reduces phosphorylation of Smads (e.g., Smad2 and / or Smad3) in cells expressing ActRII in the presence of an ActRII ligand (e.g., activin A or GDF8); (c) reduces phosphorylation of ALK4 and / or ALK7 in cells expressing ActRII and ALK4 and / or ALK7 in the presence of an ActRII ligand; and (d) a K of ≦1 nM and ≧1 pM; D (e.g., as determined by BIACORE® analysis) binds to ActRII. In some embodiments, the ActRII binding protein has two, three, or four of the above characteristics. In some embodiments, the ActRII binding protein has at least two or at least three of the above characteristics.

[0185] In some aspects, the ActRII binding protein comprises a VH having at least 90%, 95%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 144 and a VL having at least 90%, 95%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 151; and the protein binds to ActRIIB. In a further aspect, the ActRIIB binding protein has at least one characteristic selected from the group consisting of: (a) competes with an ActRII ligand (e.g., activin A, activin B, GDF1, GDF3, GDF8 (myostatin), GDF11, BMP6, BMP7, BMP9, or BMP10) for binding to ActRII; (b) reduces phosphorylation of Smads (e.g., Smad2 and / or Smad3) in cells expressing ActRII in the presence of an ActRII ligand (e.g., activin A or GDF8); (c) reduces phosphorylation of ALK4 and / or ALK7 in cells expressing ActRII and ALK4 and / or ALK7 in the presence of an ActRII ligand; and (d) a K of ≦1 nM and ≧1 pM. D (e.g., as determined by BIACORE® analysis) binds to ActRII. In some embodiments, the ActRII binding protein has two, three, or four of the above characteristics. In some embodiments, the ActRII binding protein has at least two or at least three of the above characteristics.

[0186] In some aspects, the ActRII binding protein comprises a VH having at least 90%, 95%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 165 and a VL having at least 90%, 95%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 172; the protein binds to ActIIRA and ActRIIB. In a further aspect, the ActRII binding protein has at least one characteristic selected from the group consisting of: (a) competes with an ActRII ligand (e.g., activin A, activin B, GDF1, GDF3, GDF8 (myostatin), GDF11, BMP6, BMP7, BMP9, or BMP10) for binding to ActRII; (b) reduces phosphorylation of Smads (e.g., Smad2 and / or Smad3) in cells expressing ActRII in the presence of an ActRII ligand (e.g., activin A or GDF8); (c) reduces phosphorylation of ALK4 and / or ALK7 in cells expressing ActRII and ALK4 and / or ALK7 in the presence of an ActRII ligand; and (d) a K of ≦1 nM and ≧1 pM. D (e.g., as determined by BIACORE® analysis) binds to ActRII. In some embodiments, the ActRII binding protein has two, three, or four of the above characteristics. In some embodiments, the ActRII binding protein has at least two or at least three of the above characteristics.

[0187] In some aspects, the ActRII binding protein comprises (a) a VH sequence of SEQ ID NO: 2 and a VL sequence of SEQ ID NO: 9; (b) a VH sequence of SEQ ID NO: 16 and a VL sequence of SEQ ID NO: 9; (c) a VH sequence of SEQ ID NO: 22 and a VL sequence of SEQ ID NO: 9; (d) a VH sequence of SEQ ID NO: 28 and a VL sequence of SEQ ID NO: 9; (e) a VH sequence of SEQ ID NO: 34 and a VL sequence of SEQ ID NO: 9; (f) a VH sequence of SEQ ID NO: 40 and a VL sequence of SEQ ID NO: 9; (g) a VH sequence of SEQ ID NO: 45 and a VL sequence of SEQ ID NO: 50; (h) a VH sequence of SEQ ID NO: 57 and a VL sequence of SEQ ID NO: 50; (i) a VH sequence of SEQ ID NO: 22 and a VL sequence of SEQ ID NO: 9; (j) the VH sequence of sequence number 77 and the VL sequence of sequence number 70; (k) the VH sequence of sequence number 84 and the VL sequence of sequence number 91; (l) the VH sequence of sequence number 98 and the VL sequence of sequence number 91; (m) the VH sequence of sequence number 105 and the VL sequence of sequence number 91; (n) the VH sequence of sequence number 112 and the VL sequence of sequence number 91; (o) the VH sequence of sequence number 119 and the sequence of sequence number 91; and (p) the VH sequence of sequence number 125 and the sequence of sequence number 132.

[0188] In some aspects, the ActRII binding protein comprises the VH sequence of SEQ ID NO: 144 and the VL sequence of SEQ ID NO: 151.

[0189] In some aspects, the ActRII binding protein comprises the VH sequence of SEQ ID NO: 165 and the VL sequence of SEQ ID NO: 172.

[0190] In some embodiments, an ActRII binding protein specifically binds ActRIIB and comprises a VH having at least 90%, 95%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 2, 16, 22, 28, 34, 40, 45, 57, 63, or 77. In some embodiments, an ActRII binding protein comprises a VH having at least 90%, 95%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 2. In some embodiments, an ActRII binding protein comprises a VH having at least 90%, 95%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 16. In some embodiments, an ActRII binding protein comprises a VH having at least 90%, 95%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 22. In some embodiments, an ActRII binding protein comprises a VH having at least 90%, 95%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 28. In some embodiments, an ActRII binding protein comprises a VH having at least 90%, 95%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 34. In some embodiments, an ActRII binding protein comprises a VH having at least 90%, 95%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 40. In some embodiments, an ActRII binding protein comprises a VH having at least 90%, 95%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 45. In some embodiments, an ActRII binding protein comprises a VH having at least 90%, 95%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 57. In some embodiments, the ActRII binding protein comprises a VH having at least 90%, 95%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 63. In some embodiments, the ActRII binding protein comprises a VH having at least 90%, 95%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 77.In some embodiments, the ActRII binding protein specifically binds ActRIIB and comprises a VL having at least 90%, 95%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 9, 50, or 70. In further embodiments, the ActRII binding protein specifically binds ActRIIB and comprises a VH having at least 90%, 95%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 2, 16, 22, 28, 34, or 40, and a VL having at least 90%, 95%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 9. In a further embodiment, the ActRII binding protein specifically binds ActRIIB and comprises a VH having at least 90%, 95%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 45 or 57. In some embodiments, the ActRII binding protein specifically binds ActRIIB and comprises a VL having at least 90%, 95%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 50. In further embodiments, the ActRII binding protein specifically binds ActRIIB and comprises a VH having at least 90%, 95%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 45 or 57, and a VL having at least 90%, 95%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 50. In some aspects, the ActRII binding protein specifically binds ActRIIB and comprises a VH and a VL, wherein the VH has at least 90%, 95%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 63 or 77; and the VL has at least 90%, 95%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 70. In further aspects, the ActRII binding protein specifically binds ActRIIB and comprises a VH having at least 90%, 95%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 63 or 77, and a VL having at least 90%, 95%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 70.In a further aspect, the ActRIIB binding protein has at least one characteristic selected from the group consisting of: (a) competes with an ActRII ligand (e.g., activin A, activin B, GDF1, GDF3, GDF8 (myostatin), GDF11, BMP6, BMP7, BMP9, or BMP10) for binding to ActRIIB; (b) reduces phosphorylation of Smads (e.g., Smad2 and / or Smad3) in cells expressing ActRIIB in the presence of an ActRIIB ligand (e.g., activin A or GDF8); (c) reduces phosphorylation of ALK4 and / or ALK7 in cells expressing ActRIIB and ALK4 and / or ALK7 in the presence of an ActRIIB ligand; and (d) a K of ≦1 nM and ≧1 pM. D (e.g., as determined by BIACORE® analysis) binds to ActRIIB. In some embodiments, the ActRIIB-binding protein has two, three, or four of the above characteristics. In some embodiments, the ActRIIB-binding protein has at least two or at least three of the above characteristics.

[0191] In some embodiments, an ActRII binding protein specifically binds ActRIIB and comprises a VH having at least 90%, 95%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 144. In some embodiments, an ActRII binding protein specifically binds ActRIIB and comprises a VL having at least 90%, 95%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 151. In some embodiments, an ActRII binding protein specifically binds ActRIIB and comprises a VH and a VL, wherein the VH has at least 90%, 95%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 144; and the VL has at least 90%, 95%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 151. In a further aspect, the ActRII binding protein specifically binds ActRIIB and comprises a VH having the amino acid sequence of SEQ ID NO: 144 and a VL having the amino acid sequence of SEQ ID NO: 151. In a further aspect, the ActRIIB binding protein has at least one characteristic selected from the group consisting of: (a) competes with an ActRII ligand (e.g., activin A, activin B, GDF1, GDF3, GDF8 (myostatin), GDF11, BMP6, BMP7, BMP9, or BMP10) for binding to ActRIIB; (b) reduces phosphorylation of Smads (e.g., Smad2 and / or Smad3) in cells expressing ActRIIB in the presence of an ActRIIB ligand (e.g., activin A or GDF8); (c) reduces phosphorylation of ALK4 and / or ALK7 in cells expressing ActRIIB and ALK4 and / or ALK7 in the presence of an ActRIIB ligand; and (d) a K of ≦1 nM and ≧1 pM. D (e.g., as determined by BIACORE® analysis) binds to ActRIIB. In some embodiments, the ActRIIB-binding protein has two, three, or four of the above characteristics. In some embodiments, the ActRIIB-binding protein has at least two or at least three of the above characteristics.

[0192] In some embodiments, an ActRII binding protein specifically binds ActIIRA and ActRIIB and comprises a VH having at least 90%, 95%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 165. In some embodiments, an ActRII binding protein specifically binds ActIIRA and ActRIIB and comprises a VL having at least 90%, 95%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 172. In some embodiments, an ActRII binding protein specifically binds ActIIRA and ActRIIB and comprises a VH and a VL, wherein the VH has at least 90%, 95%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 165; and the VL has at least 90%, 95%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 172. In a further aspect, the ActRII binding protein specifically binds ActIIRA and ActRIIB and comprises a VH having the amino acid sequence of SEQ ID NO: 165 and a VL having the amino acid sequence of SEQ ID NO: 172. In a further aspect, the ActRII binding protein has at least one characteristic selected from the group consisting of: (a) competing with an ActRII ligand (e.g., activin A, activin B, GDF1, GDF3, GDF8 (myostatin), GDF11, BMP6, BMP7, BMP9, or BMP10) for binding to ActRIIA and / or ActRIIB; (b) reducing phosphorylation of Smads (e.g., Smad2 and / or Smad3) in cells expressing ActRIIA and / or ActRIIB in the presence of an ActRIIA and / or ActRIIB ligand (e.g., activin A or GDF8); (c) reducing phosphorylation of ALK4 and / or ALK7 in cells expressing ActRIIA and / or ActRIIB and ALK4 and / or ALK7 in the presence of an ActRIIA and / or ActRIIB ligand; and (d) a K of ≦1 nM and ≧1 pM. D(e.g., as determined by BIACORE® analysis) binds to each of ActRIIA and ActRIIB. In some embodiments, the ActRII binding protein has two, three, or four of the above characteristics. In some embodiments, the ActRII binding protein has at least two or at least three of the above characteristics.

[0193] In some embodiments, an ActRII binding protein specifically binds ActRIIB and ActRIIA and comprises a VH having at least 90%, 95%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 84, 98, 105, 112, or 119. In some embodiments, an ActRII binding protein specifically binds ActRIIB and ActRIIA and comprises a VH having at least 90%, 95%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 84. In some embodiments, an ActRII binding protein specifically binds ActRIIB and ActRIIA and comprises a VH having at least 90%, 95%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 98. In some embodiments, an ActRII binding protein specifically binds ActRIIB and ActRIIA and comprises a VH having at least 90%, 95%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 105. In some embodiments, an ActRII binding protein specifically binds ActRIIB and ActRIIA and comprises a VH having at least 90%, 95%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 112. In some embodiments, an ActRII binding protein specifically binds ActRIIB and ActRIIA and comprises a VH having at least 90%, 95%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 119. In some embodiments, an ActRII binding protein specifically binds ActRIIB and ActRIIA and comprises a VL having at least 90%, 95%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 91. In a further aspect, the ActRII binding protein specifically binds to ActRIIB and ActRIIA and comprises a VH having at least 90%, 95%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 84, 98, 105, 112, or 119, and a VL having at least 90%, 95%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 91.In a further aspect, the ActRII binding protein specifically binds ActRIIB and ActRIIA and comprises a VH having at least 90%, 95%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 84 and a VL having at least 90%, 95%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 91. In a further aspect, the ActRII binding protein specifically binds ActRIIB and ActRIIA and comprises a VH having at least 90%, 95%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 98 and a VL having at least 90%, 95%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 91. In a further aspect, the ActRII binding protein specifically binds ActRIIB and ActRIIA and comprises a VH having at least 90%, 95%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 105 and a VL having at least 90%, 95%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 91. In a further aspect, the ActRII binding protein specifically binds ActRIIB and / or ActRIIA and comprises a VH having at least 90%, 95%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 112 and a VL having at least 90%, 95%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 91. In a further aspect, the ActRII binding protein specifically binds to ActRIIB and ActRIIA and comprises a VH having at least 90%, 95%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 119, and a VL having at least 90%, 95%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 91.In a further aspect, the ActRIIB and ActRIIA binding proteins have at least one characteristic selected from the group consisting of: (a) competing with an ActRII ligand (e.g., activin A, activin B, GDF1, GDF3, GDF8 (myostatin), GDF11, BMP6, BMP7, BMP9, or BMP10) for binding to ActRIIB and ActRIIA; (b) competing with an ActRII ligand (e.g., activin A, activin B, GDF1, GDF3, GDF8 (myostatin), GDF11, BMP6, BMP7, BMP9, or BMP10) for binding to ActRIIB and ActRIIA in the presence of an ActRIIB and / or ActRIIA ligand (e.g., activin A or GDF8). (c) reduces phosphorylation of Smads (e.g., Smad2 and / or Smad3) in cells expressing ActRIIB and / or ActRIIA; (c) reduces phosphorylation of ALK4 and / or ALK7 in cells expressing ActRIIB and / or ActRIIA and ALK4 and / or ALK7 in the presence of an ActRIIB and / or ActRIIA ligand; and (d) binds to ActRIIB and / or ActRIIA with a KD of ≦1 nM and ≧1 pM (e.g., as determined by BIACORE® analysis). In some embodiments, ActRIIB and ActRIIA binding proteins have two, three, or four of the above characteristics. In some embodiments, ActRIIB and ActRIIA binding proteins have at least two or at least three of the above characteristics.

[0194] In some embodiments, an ActRII binding protein specifically binds ActRIIA and comprises a VH having at least 90%, 95%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 125. In some embodiments, an ActRII binding protein specifically binds ActRIIA and comprises a VL having at least 90%, 95%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 132. In some embodiments, an ActRII binding protein specifically binds ActRIIA and comprises a VH and a VL, wherein the VH has at least 90%, 95%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 125; and the VL has at least 90%, 95%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 132. In further embodiments, the ActRIIA binding protein has at least one characteristic selected from the group consisting of: (a) competes with an ActRIIA ligand (e.g., activin A, activin B, GDF1, GDF3, or Nodal); (b) reduces phosphorylation of Smads (e.g., Smad2 and / or Smad3) in cells expressing ActRIIA in the presence of an ActRIIA ligand (e.g., activin A); (c) reduces phosphorylation of ALK4 and / or ALK7 in cells expressing ActRIIA and ALK4 and / or ALK7 in the presence of an ActRIIA ligand; and (d) binds to ActRIIA with a KD of ≦1 nM and ≧1 pM (e.g., as determined by BIACORE® analysis). In some embodiments, the ActRIIA binding protein has two, three, or four of the above characteristics. In some embodiments, the ActRIIA binding protein has at least two or at least three of the above characteristics.

[0195] In a further aspect, the ActRII binding protein competes for binding to ActRII with an antibody comprising a VH and VL sequence pair disclosed herein. In a further aspect, the ActRII binding protein competes for binding to ActRII with an antibody comprising a VH and VL sequence pair disclosed in Table 1. In certain aspects, the ActRII binding protein binds to the same epitope as an ActRII binding protein disclosed herein. In a further aspect, the ActRII binding protein binds to the same epitope as an ActRII binding protein disclosed in Table 1. The ability of an ActRII binding protein to compete for binding to and / or bind to the same epitope on ActRII as a reference ActRII binding protein can be readily determined using techniques disclosed herein or alternatively known in the art.

[0196] In some embodiments, the ActRII binding protein specifically binds ActRIIB and comprises a VH of SEQ ID NO: 2, 16, 22, 28, 34, 40, 45, 57, 63, or 77. In further embodiments, the ActRII binding protein specifically binds ActRIIB and comprises a VL of SEQ ID NO: 9, 50, or 70. In further embodiments, the ActRII binding protein specifically binds ActRIIB and comprises a VH of SEQ ID NO: 2, 16, 22, 28, 34, 40, 45, 57, 63, or 77; and a VL of SEQ ID NO: 9, 50, or 70. In some embodiments, the ActRII binding protein specifically binds ActRIIB and comprises a VH of SEQ ID NO: 144. In a further embodiment, the ActRII binding protein specifically binds ActRIIB and comprises a VL of SEQ ID NO: 151. In further aspects, the ActRII binding protein specifically binds ActRIIB and comprises a VH of SEQ ID NO: 144 and a VL of SEQ ID NO: 151. In further aspects, the ActRII binding protein specifically binds ActRIIB but not ActRIIA. In some aspects, the ActRII binding protein specifically binds ActRIIA and comprises ActRIIB and a VH of SEQ ID NO: 165. In further aspects, the ActRII binding protein specifically binds ActRIIA and comprises ActRIIB and a VL of SEQ ID NO: 172. In further aspects, the ActRII binding protein specifically binds ActRIIA and comprises ActRIIB and a VH of SEQ ID NO: 165 and a VL of SEQ ID NO: 172. In further aspects, the ActRII binding protein specifically binds ActRIIA and ActRIIB.

[0197] In some aspects, the ActRII binding protein binds to amino acid residue NANWELERT (SEQ ID NO: 157) of ActRIIB. In some aspects, the ActRII binding protein binds to amino acid residue NANWELERT (SEQ ID NO: 157) of ActRIIB, but does not bind to AcRIIA. In some aspects, the ActRII binding protein binds to amino acid residue VKKGCWLDD (SEQ ID NO: 158) of ActRIIB, but does not bind to AcRIIA. In some aspects, the ActRII binding protein binds to amino acid residue NANWELERT (SEQ ID NO: 157) and amino acid residue VKKGCWLDD (SEQ ID NO: 158) of ActRIIB. In further aspects, the ActRII binding protein binds to amino acid residue NANWELERT (SEQ ID NO: 157) and amino acid residue VKKGCWLDD (SEQ ID NO: 158) of ActRIIB, but does not bind to ActRIIA.

[0198] In some aspects, the ActRII binding protein binds to a polypeptide selected from the group consisting of: (a) amino acid residue NANWELERT (SEQ ID NO: 157) of ActRIIB; (b) amino acid residue CCEGNFCNER (SEQ ID NO: 159) of ActRIIB; (c) amino acid residue CCEGNMCNEK (SEQ ID NO: 161) of ActRIIA; and (d) amino acid residue ECLFFNANWEKD (SEQ ID NO: 162) of ActRIIA.

[0199] In some embodiments, the ActRII binding protein binds to a polypeptide or set of polypeptides selected from the group consisting of: (a) amino acid residue NANWELERT (SEQ ID NO: 157) and amino acid residue CCEGNFCNER (SEQ ID NO: 159) of ActRIIB; (b) amino acid residue NANWELERT (SEQ ID NO: 157) and amino acid residue VKKGCWLDD (SEQ ID NO: 158) of ActRIIB; (c) amino acid residue NANWELERT (SEQ ID NO: 157), amino acid residue CCEGNFCNER (SEQ ID NO: 159), and amino acid residue GCWLDDFNCYDR (SEQ ID NO: 160) of ActRIIB; (d) amino acid residue NANWELERT (SEQ ID NO: 157) of ActRIIB and amino acid residue ECLFFNANWEKD (SEQ ID NO: 162) of ActRIIA; (e) amino acid residue NANWELERT (SEQ ID NO: 157) and amino acid residue GC WLDDFNCYDR (sequence number 160), and amino acid residue VKKGCWLDD (sequence number 158); (f) amino acid residue CCEGNFCNER (sequence number 159) of ActRIIB and amino acid residue CCEGNMCNEK (sequence number 161) of ActRIIA; (g) amino acid residue CCEGNMCNEK (sequence number 161), amino acid residue ECLFFNANWEKD (sequence number 162), and amino acid residue CWLDDINCYDRT (sequence number 163) of ActRIIA; (h) amino acid residue NANWELERT (sequence number 157), amino acid residue CCEGNFCNER (sequence number 159), and amino acid residue GCWLDDFNCYDR (sequence number 160) of ActRIIB, and amino acid residue CCEGNMCNEK (sequence number 161), amino acid residue ECLFFNANWEKD (sequence number 162), and amino acid residue CWLDDINCYDRT (sequence number 163) of ActRIIA.

[0200] In some embodiments, the ActRII binding protein competes for binding to ActRIIB with an antibody comprising a VH of SEQ ID NO: 2, 16, 22, 28, 34, 40, 45, 57, 63, 77, or 144 and a VL of SEQ ID NO: 9, 50, 70, or 151. In further embodiments, the ActRII binding protein binds to the same epitope on ActRIIB and / or ActRIIA as an antibody comprising a VH of SEQ ID NO: 2, 16, 22, 28, 34, 40, 45, 57, 63, 77, or 144 and a VL of SEQ ID NO: 9, 50, 70, or 151.

[0201] In some aspects, an ActRIIB binding protein (e.g., an anti-ActRIIB antibody) comprises a VH of SEQ ID NO: 2 and a VL of SEQ ID NO: 9. In some aspects, the ActRIIB binding protein competes for binding to ActRIIB with an antibody comprising a VH of SEQ ID NO: 2 and a VL of SEQ ID NO: 9. In further aspects, the ActRII binding protein binds to the same epitope of ActRIIB as an antibody comprising a VH of SEQ ID NO: 2 and a VL of SEQ ID NO: 9.

[0202] In some embodiments, the ActRIIB binding protein comprises a VH of SEQ ID NO: 16 and a VL of SEQ ID NO: 9. In some embodiments, the ActRIIB binding protein competes for binding to ActRIIB with an antibody comprising a VH of SEQ ID NO: 16 and a VL of SEQ ID NO: 9. In further embodiments, the ActRII binding protein binds to the same epitope of ActRIIB as an antibody comprising a VH of SEQ ID NO: 16 and a VL of SEQ ID NO: 9.

[0203] In some embodiments, the ActRIIB binding protein comprises a VH of SEQ ID NO: 22 and a VL of SEQ ID NO: 9. In some embodiments, the ActRIIB binding protein competes for binding to ActRIIB with an antibody comprising a VH of SEQ ID NO: 22 and a VL of SEQ ID NO: 9. In further embodiments, the ActRII binding protein binds to the same epitope of ActRIIB as an antibody comprising a VH of SEQ ID NO: 22 and a VL of SEQ ID NO: 9.

[0204] In some embodiments, the ActRIIB binding protein comprises a VH of SEQ ID NO: 28 and a VL of SEQ ID NO: 9. In some embodiments, the ActRIIB binding protein competes for binding to ActRIIB with an antibody comprising a VH of SEQ ID NO: 28 and a VL of SEQ ID NO: 9. In further embodiments, the ActRII binding protein binds to the same epitope of ActRIIB as an antibody comprising a VH of SEQ ID NO: 28 and a VL of SEQ ID NO: 9.

[0205] In some embodiments, the ActRIIB binding protein comprises a VH of SEQ ID NO: 34 and a VL of SEQ ID NO: 9. In some embodiments, the ActRIIB binding protein competes for binding to ActRIIB with an antibody comprising a VH of SEQ ID NO: 34 and a VL of SEQ ID NO: 9. In further embodiments, the ActRII binding protein binds to the same epitope of ActRIIB as an antibody comprising a VH of SEQ ID NO: 34 and a VL of SEQ ID NO: 9.

[0206] In some embodiments, the ActRIIB binding protein comprises a VH of SEQ ID NO: 40 and a VL of SEQ ID NO: 9. In some embodiments, the ActRIIB binding protein competes for binding to ActRIIB with an antibody comprising a VH of SEQ ID NO: 40 and a VL of SEQ ID NO: 9. In further embodiments, the ActRII binding protein binds to the same epitope of ActRIIB as an antibody comprising a VH of SEQ ID NO: 40 and a VL of SEQ ID NO: 9.

[0207] In some embodiments, the ActRIIB binding protein comprises a VH of SEQ ID NO: 45 and a VL of SEQ ID NO: 50. In some embodiments, the ActRIIB binding protein competes for binding to ActRIIB with an antibody comprising a VH of SEQ ID NO: 45 and a VL of SEQ ID NO: 50. In further embodiments, the ActRII binding protein binds to the same epitope of ActRIIB as an antibody comprising a VH of SEQ ID NO: 45 and a VL of SEQ ID NO: 50.

[0208] In some embodiments, the ActRIIB binding protein comprises a VH of SEQ ID NO: 57 and a VL of SEQ ID NO: 50. In some embodiments, the ActRIIB binding protein competes for binding to ActRIIB with an antibody comprising a VH of SEQ ID NO: 57 and a VL of SEQ ID NO: 50. In further embodiments, the ActRII binding protein binds to the same epitope on ActRIIB as an antibody comprising a VH of SEQ ID NO: 57 and a VL of SEQ ID NO: 50.

[0209] In some embodiments, the ActRIIB binding protein comprises a VH of SEQ ID NO: 63 and a VL of SEQ ID NO: 70. In some embodiments, the ActRIIB binding protein competes for binding to ActRIIB with an antibody comprising a VH of SEQ ID NO: 63 and a VL of SEQ ID NO: 70. In further embodiments, the ActRII binding protein binds to the same epitope on ActRIIB as an antibody comprising a VH of SEQ ID NO: 63 and a VL of SEQ ID NO: 70.

[0210] In some embodiments, the ActRIIB binding protein comprises a VH of SEQ ID NO: 77 and a VL of SEQ ID NO: 70. In some embodiments, the ActRIIB binding protein competes for binding to ActRIIB with an antibody comprising a VH of SEQ ID NO: 77 and a VL of SEQ ID NO: 70. In further embodiments, the ActRII binding protein binds to the same epitope on ActRIIB as an antibody comprising a VH of SEQ ID NO: 77 and a VL of SEQ ID NO: 70.

[0211] In some embodiments, the ActRIIB binding protein comprises a VH of SEQ ID NO: 144 and a VL of SEQ ID NO: 151. In some embodiments, the ActRIIB binding protein competes for binding to ActRIIB with an antibody comprising a VH of SEQ ID NO: 144 and a VL of SEQ ID NO: 151. In further embodiments, the ActRII binding protein binds to the same epitope of ActRIIB as an antibody comprising a VH of SEQ ID NO: 144 and a VL of SEQ ID NO: 151.

[0212] In some embodiments, the ActRII binding protein comprises a VH of SEQ ID NO: 165 and a VL of SEQ ID NO: 172. In some embodiments, the ActRIIB binding protein competes for binding to ActRIIB with an antibody comprising a VH of SEQ ID NO: 165 and a VL of SEQ ID NO: 172. In further embodiments, the ActRII binding protein binds to the same epitope of ActRIIB as an antibody comprising a VH of SEQ ID NO: 165 and a VL of SEQ ID NO: 172.

[0213] In some embodiments, the ActRII binding protein comprises a VH of SEQ ID NO: 165 and a VL of SEQ ID NO: 172. In some embodiments, the ActRIIA binding protein competes for binding to ActRIIA with an antibody comprising a VH of SEQ ID NO: 165 and a VL of SEQ ID NO: 172. In further embodiments, the ActRII binding protein binds to the same epitope of ActRIIA as an antibody comprising a VH of SEQ ID NO: 165 and a VL of SEQ ID NO: 172.

[0214] In some aspects, the ActRIIB binding protein competes with an antibody comprising a VH of SEQ ID NO: 144 and a VL of SEQ ID NO: 151 for binding to amino acid residues NANWELERT (SEQ ID NO: 157) of ActRIIB. In some aspects, the ActRIIB binding protein competes with an antibody comprising a VH of SEQ ID NO: 144 and a VL of SEQ ID NO: 151 for binding to amino acid residues VKKGCWLDD (SEQ ID NO: 158) of ActRIIB. In some aspects, the ActRIIB binding protein competes with an antibody comprising a VH of SEQ ID NO: 144 and a VL of SEQ ID NO: 151 for binding to amino acid residues NANWELERT (SEQ ID NO: 157) and amino acid residues VKKGCWLDD (SEQ ID NO: 158) of ActRIIB. In a further aspect, the ActRIIB binding protein does not specifically bind to ActRIIA.

[0215] In some aspects, the ActRII binding protein competes for binding to ActRIIB and / or ActRIIA with an antibody comprising a VH of SEQ ID NO: 84, 98, 105, 112, or 119 and a VL of SEQ ID NO: 91. In further aspects, the ActRII binding protein binds to the same epitope of ActRIIB and / or ActRIIA as an antibody comprising a VH of SEQ ID NO: 84, 98, 105, 112, or 119; and a VL of SEQ ID NO: 91.

[0216] In some embodiments, the ActRII binding protein binds to amino acid residue CCEGNFCNER (SEQ ID NO: 159) of ActRIIB.

[0217] In some embodiments, the ActRII binding protein binds to amino acid residue GCWLDDFNCYDR (SEQ ID NO: 160) of ActRIIB.

[0218] In some aspects, an ActRII binding protein binds to amino acid residue NANWELERT (SEQ ID NO: 157) of ActRIIB. In some aspects, an ActRII binding protein binds to amino acid residue NANWELERT (SEQ ID NO: 157) and amino acid residue GCWLDDFNCYDR (SEQ ID NO: 160) of ActRIIB. In some embodiments, an ActRII binding protein binds to amino acid residue NANWELERT (SEQ ID NO: 157) and amino acid residue CCEGNFCNER (SEQ ID NO: 159) of ActRIIB. In further embodiments, an ActRII binding protein binds to amino acid residue NANWELERT (SEQ ID NO: 157), amino acid residue CCEGNFCNER (SEQ ID NO: 159), and amino acid residue GCWLDDFNCYDR (SEQ ID NO: 160) of ActRIIB.

[0219] In some embodiments, the ActRII binding protein binds to amino acid residues CCEGNMCNEK (SEQ ID NO: 161) of ActRIIA.

[0220] In some embodiments, the ActRII binding protein binds to amino acid residues ECLFFNANWEKD (SEQ ID NO: 162) of ActRIIA. In further embodiments, the ActRII binding protein binds to amino acid residues CCEGNMCNEK (SEQ ID NO: 161) and amino acid residues ECLFFNANWEKD (SEQ ID NO: 162) of ActRIIA.

[0221] In some aspects, the ActRII binding protein binds to amino acid residue CWLDDINCYDRT (SEQ ID NO: 163) of ActRIIA. In further embodiments, the ActRII binding protein binds to amino acid residue CCEGNMCNEK (SEQ ID NO: 161), amino acid residue ECLFFNANWEKD (SEQ ID NO: 162), and amino acid residue CWLDDINCYDRT (SEQ ID NO: 163) of ActRIIA.

[0222] In some aspects, the ActRII binding protein binds to amino acid residues CCEGNFCNER (SEQ ID NO: 159) of ActRIIB and CCEGNMCNEK (SEQ ID NO: 161) of ActRIIA.

[0223] In some aspects, the ActRII binding protein binds to amino acid residue NANWELERT (SEQ ID NO: 157) of ActRIIB and amino acid residue ECLFFNANWEKD (SEQ ID NO: 162) of ActRIIA. In further aspects, the ActRII binding protein binds to amino acid residue CCEGNFCNER (SEQ ID NO: 159) and amino acid residue NANWELERT (SEQ ID NO: 157) of ActRIIB, and amino acid residue CCEGNMCNEK (SEQ ID NO: 161) and amino acid residue ECLFFNANWEKD (SEQ ID NO: 162) of ActRIIA. In a further aspect, the ActRII binding protein binds to amino acid residues CCEGNFCNER (SEQ ID NO: 159), amino acid residues NANWELERT (SEQ ID NO: 157) of ActRIIB, and amino acid residues GCWLDDFNCYDR (SEQ ID NO: 160) and amino acid residues CCEGNMCNEK (SEQ ID NO: 161), amino acid residues ECLFFNANWEKD (SEQ ID NO: 162), and amino acid residues CWLDDINCYDRT (SEQ ID NO: 163) of ActRIIA.

[0224] In some aspects, the ActRIIB and ActRIIA binding protein comprises a VH of SEQ ID NO: 84 and a VL of SEQ ID NO: 91. In some aspects, the ActRIIB binding protein competes for binding to ActRIIB and ActRIIA with an antibody comprising a VH of SEQ ID NO: 84 and a VL of SEQ ID NO: 91. In further aspects, the ActRII binding protein binds to the same epitope of ActRIIB and ActRIIA as an antibody comprising a VH of SEQ ID NO: 84 and a VL of SEQ ID NO: 91.

[0225] In some aspects, the ActRIIB and ActRIIA binding protein comprises a VH of SEQ ID NO: 165 and a VL of SEQ ID NO: 172. In some aspects, the ActRIIB binding protein competes for binding to ActRIIB and ActRIIA with an antibody comprising a VH of SEQ ID NO: 165 and a VL of SEQ ID NO: 172. In further aspects, the ActRII binding protein binds to the same epitope of ActRIIB and ActRIIA as an antibody comprising a VH of SEQ ID NO: 165 and a VL of SEQ ID NO: 172.

[0226] In some aspects, the ActRIIB and ActRIIA binding proteins compete for binding to amino acid residues CCEGNFCNER (SEQ ID NO: 159) of ActRIIB with an antibody comprising a VH of SEQ ID NO: 84 and a VL of SEQ ID NO: 91. In some aspects, the ActRIIB and ActRIIA binding proteins compete for binding to amino acid residues NANWELERT (SEQ ID NO: 157) of ActRIIB with an antibody comprising a VH of SEQ ID NO: 84 and a VL of SEQ ID NO: 91. In further aspects, the ActRIIB and ActRIIA binding proteins compete for binding to amino acid residues CCEGNFCNER (SEQ ID NO: 159) and amino acid residues NANWELERT (SEQ ID NO: 157) of ActRIIB with an antibody comprising a VH of SEQ ID NO: 84 and a VL of SEQ ID NO: 91.

[0227] In some aspects, the ActRIIB and ActRIIA binding proteins compete for binding to amino acid residues CCEGNFCNER (SEQ ID NO: 159) of ActRIIB with an antibody comprising a VH of SEQ ID NO: 165 and a VL of SEQ ID NO: 172. In some aspects, the ActRIIB and ActRIIA binding proteins compete for binding to amino acid residues NANWELERT (SEQ ID NO: 157) of ActRIIB with an antibody comprising a VH of SEQ ID NO: 165 and a VL of SEQ ID NO: 172. In further aspects, the ActRIIB and ActRIIA binding proteins compete for binding to amino acid residues CCEGNFCNER (SEQ ID NO: 159) and amino acid residues NANWELERT (SEQ ID NO: 157) of ActRIIB with an antibody comprising a VH of SEQ ID NO: 165 and a VL of SEQ ID NO: 172.

[0228] In some aspects, the ActRIIB and ActRIIA binding proteins compete with an antibody comprising a VH of SEQ ID NO: 84 and a VL of SEQ ID NO: 91 for binding to amino acid residues GCWLDDFNCYDR (SEQ ID NO: 160) of ActRIIB.

[0229] In some aspects, the ActRIIB and ActRIIA binding proteins compete with an antibody comprising a VH of SEQ ID NO: 165 and a VL of SEQ ID NO: 172 for binding to amino acid residues GCWLDDFNCYDR (SEQ ID NO: 160) of ActRIIB.

[0230] In some aspects, ActRIIB and ActRIIA binding proteins compete with an antibody comprising a VH of SEQ ID NO: 84 and a VL of SEQ ID NO: 91 for binding to amino acid residues CCEGNFCNER (SEQ ID NO: 159), amino acid residues NANWELERT (SEQ ID NO: 157), and amino acid residues GCWLDDFNCYDR (SEQ ID NO: 160) of ActRIIB.

[0231] In some aspects, ActRIIB and ActRIIA binding proteins compete with an antibody comprising a VH of SEQ ID NO: 165 and a VL of SEQ ID NO: 172 for binding to amino acid residues CCEGNFCNER (SEQ ID NO: 159), amino acid residues NANWELERT (SEQ ID NO: 157), and amino acid residues GCWLDDFNCYDR (SEQ ID NO: 160) of ActRIIB.

[0232] In some embodiments, the ActRII binding protein specifically binds ActRIIB and ActRIIA and comprises a VH of SEQ ID NO: 84, 98, 105, 112, or 119. In further embodiments, the ActRII binding protein specifically binds ActRIIB and ActRIIA and comprises a VL of SEQ ID NO: 91. In a further embodiment, the ActRII binding protein specifically binds ActRIIB and ActRIIA and comprises a VH of SEQ ID NO: 84, 98, 105, 112, or 119; and a VL of SEQ ID NO: 91.

[0233] In some aspects, the ActRII binding protein specifically binds ActRIIB and ActRIIA and comprises a VH of SEQ ID NO: 165. In further aspects, the ActRII binding protein specifically binds ActRIIB and ActRIIA and comprises a VL of SEQ ID NO: 172. In further aspects, the ActRII binding protein specifically binds ActRIIB and ActRIIA and comprises a VH of SEQ ID NO: 165; and a VL of SEQ ID NO: 172.

[0234] In some aspects, the ActRIIB and ActRIIA binding proteins comprise a VH of SEQ ID NO: 84 and a VL of SEQ ID NO: 91. In further aspects, the ActRII binding proteins bind to the same epitope of ActRIIB and ActRIIA as an antibody comprising a VH of SEQ ID NO: 84 and a VL of SEQ ID NO: 91.

[0235] In some aspects, the ActRIIB and ActRIIA binding protein comprises a VH of SEQ ID NO: 98 and a VL of SEQ ID NO: 91. In some aspects, the ActRIIB binding protein competes for binding to ActRIIB and ActRIIA with an antibody comprising a VH of SEQ ID NO: 98 and a VL of SEQ ID NO: 91. In further aspects, the ActRII binding protein binds to the same epitope of ActRIIB and ActRIIA as an antibody comprising a VH of SEQ ID NO: 98 and a VL of SEQ ID NO: 91.

[0236] In some aspects, the ActRIIB and ActRIIA binding protein comprises a VH of SEQ ID NO: 105 and a VL of SEQ ID NO: 91. In some aspects, the ActRIIB binding protein competes for binding to ActRIIB and ActRIIA with an antibody comprising a VH of SEQ ID NO: 105 and a VL of SEQ ID NO: 91. In further aspects, the ActRII binding protein binds to the same epitope of ActRIIB and ActRIIA as an antibody comprising a VH of SEQ ID NO: 105 and a VL of SEQ ID NO: 91.

[0237] In some aspects, the ActRIIB and ActRIIA binding protein comprises a VH of SEQ ID NO: 112 and a VL of SEQ ID NO: 91. In some aspects, the ActRIIB binding protein competes for binding to ActRIIB and ActRIIA with an antibody comprising a VH of SEQ ID NO: 112 and a VL of SEQ ID NO: 91. In further aspects, the ActRII binding protein binds to the same epitope of ActRIIB and ActRIIA as an antibody comprising a VH of SEQ ID NO: 112 and a VL of SEQ ID NO: 91.

[0238] In some aspects, the ActRIIB and ActRIIA binding protein comprises a VH of SEQ ID NO: 119 and a VL of SEQ ID NO: 91. In some aspects, the ActRIIB binding protein competes for binding to ActRIIB and ActRIIA with an antibody comprising a VH of SEQ ID NO: 119 and a VL of SEQ ID NO: 91. In further aspects, the ActRII binding protein binds to the same epitope of ActRIIB and ActRIIA as an antibody comprising a VH of SEQ ID NO: 119 and a VL of SEQ ID NO: 91.

[0239] In some embodiments, the ActRIIA binding protein comprises a VH of SEQ ID NO: 125 and a VL of SEQ ID NO: 132. In some embodiments, the ActRIIA binding protein competes for binding to ActRIIA with an antibody comprising a VH of SEQ ID NO: 125 and a VL of SEQ ID NO: 132. In further embodiments, the ActRII binding protein binds to the same epitope of ActRIIA as an antibody comprising a VH of SEQ ID NO: 125 and a VL of SEQ ID NO: 132.

[0240] In some embodiments, the ActRII binding protein specifically binds ActRIIB and comprises a set of CDRs: VH-CDR1, VH-CDR2, and VH-CDR3, where the set of CDRs is identical to or has a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or fewer than 10 amino acid substitutions, deletions, and / or insertions from the reference set of CDRs. The reference set of CDRs has: (a) VH-CDR1 having the amino acid sequence of SEQ ID NO: 3 or 58; (b) VH-CDR2 having the amino acid sequence of SEQ ID NO: 4 or 59; or (c) VH-CDR3 having the amino acid sequence of SEQ ID NO: 46. In a further aspect, the ActRIIB binding protein has at least one characteristic selected from the group consisting of: (a) competes with an ActRII ligand (e.g., activin A, activin B, GDF1, GDF3, GDF8 (myostatin), GDF11, BMP6, BMP7, BMP9, or BMP10) for binding to ActRIIB; (b) decreases phosphorylation of Smads (e.g., Smad2 and / or Smad3) in cells expressing ActRIIB in the presence of an ActRIIB ligand (e.g., activin A or GDF8); (c) decreases phosphorylation of ALK4 and / or ALK7 in cells expressing ActRIIB and ALK4 and / or ALK7 in the presence of an ActRIIB ligand; and (d) a K of ≦1 nM and ≦1 pM. D (e.g., as determined by BIACORE® analysis) binds to ActRIIB. In some embodiments, the ActRIIB-binding protein has two, three, or four of the above characteristics. In some embodiments, the ActRIIB-binding protein has at least two or at least three of the above characteristics.

[0241] In some embodiments, the ActRII binding protein specifically binds ActRIIB and comprises a set of CDRs: VL-CDR1, VL-CDR2, and VL-CDR3, where the set of CDRs is identical to or has a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or fewer than 10 amino acid substitutions, deletions, and / or insertions from the reference set of CDRs. The reference set of CDRs has: (a) VL-CDR1 having the amino acid sequence of SEQ ID NO: 51; (b) VL-CDR2 having the amino acid sequence of SEQ ID NO: 52; or (c) VL-CDR3 having the amino acid sequence of SEQ ID NO: 53. In a further aspect, the ActRIIB binding protein has at least one characteristic selected from the group consisting of: (a) competes with an ActRII ligand (e.g., activin A, activin B, GDF1, GDF3, GDF8 (myostatin), GDF11, BMP6, BMP7, BMP9, or BMP10) for binding to ActRIIB; (b) reduces phosphorylation of Smads (e.g., Smad2 and / or Smad3) in cells expressing ActRIIB in the presence of an ActRIIB ligand (e.g., activin A or GDF8); (c) reduces phosphorylation of ALK4 and / or ALK7 in cells expressing ActRIIB and ALK4 and / or ALK7 in the presence of an ActRIIB ligand; and (d) a K of ≦1 nM and ≧1 pM. D (e.g., as determined by BIACORE® analysis) binds to ActRIIB. In some embodiments, the ActRIIB-binding protein has two, three, or four of the above characteristics. In some embodiments, the ActRIIB-binding protein has at least two or at least three of the above characteristics.

[0242] In a further aspect, the ActRII binding protein specifically binds to ActRIIB and comprises a CDR set: VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2, and VL-CDR3, wherein the CDR set is identical to the reference set of CDRs or has a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or fewer than 10 amino acid substitutions, deletions, and / or insertions from the reference set of CDRs. The reference set of CDRs has (a) VH-CDR1 having the amino acid sequence of SEQ ID NO: 3 or 58; (b) VH-CDR2 having the amino acid sequence of SEQ ID NO: 4 or 59; (c) VH-CDR3 having the amino acid sequence of SEQ ID NO: 46; (d) VL-CDR1 having the amino acid sequence of SEQ ID NO: 51; (e) VL-CDR2 having the amino acid sequence of SEQ ID NO: 52; or (f) VL-CDR3 having the amino acid sequence of SEQ ID NO: 53. In a further aspect, the ActRIIB binding protein has at least one characteristic selected from the group consisting of: (a) competes with an ActRII ligand (e.g., activin A, activin B, GDF1, GDF3, GDF8 (myostatin), GDF11, BMP6, BMP7, BMP9, or BMP10) for binding to ActRIIB; (b) reduces phosphorylation of Smads (e.g., Smad2 and / or Smad3) in cells expressing ActRIIB in the presence of an ActRIIB ligand (e.g., activin A or GDF8); (c) reduces phosphorylation of ALK4 and / or ALK7 in cells expressing ActRIIB and ALK4 and / or ALK7 in the presence of an ActRIIB ligand; and (d) a K of ≦1 nM and ≧1 pM. D (e.g., as determined by BIACORE® analysis) binds to ActRIIB. In some embodiments, the ActRIIB-binding protein has two, three, or four of the above characteristics. In some embodiments, the ActRIIB-binding protein has at least two or at least three of the above characteristics.

[0243] In a further aspect, the ActRII binding protein specifically binds ActRIIB and ActRIIA and comprises a VH antigen binding domain (ABD) set: VH-ABD1, VH-ABD2, VH-ABD3, VL-ABD1, VL-ABD2, and VL-ABD3, wherein the ABD set is (a) VH-ABD1 having the amino acid sequence of SEQ ID NO: 140; (b) VH-ABD2 having the amino acid sequence of SEQ ID NO: 141; (c) VH-ABD3 having the amino acid sequence of SEQ ID NO: 142; (d) VL-ABD1 having the amino acid sequence of SEQ ID NO: 92; (e) VL-ABD2 having the amino acid sequence of SEQ ID NO: 93; or (f) VL-ABD3 having the amino acid sequence of SEQ ID NO: 94. In a further aspect, the ActRIIB binding protein comprises a VH and a VL. In a further aspect, the ActRIIB and ActRIIA binding proteins have at least one characteristic selected from the group consisting of: (a) compete with an ActRII ligand (e.g., activin A, activin B, GDF1, GDF3, GDF8 (myostatin), GDF11, BMP6, BMP7, BMP9, or BMP10) for binding to ActRIIB or ActRIIA; (b) decrease phosphorylation of Smads (e.g., Smad2 and / or Smad3) in cells expressing ActRIIB and / or ActRIIA in the presence of an ActRIIB and / or ActRIIA ligand (e.g., activin A); (c) decrease phosphorylation of ALK4 and / or ALK7 in cells expressing ActRIIB and / or ActRIIA and ALK4 and / or ALK7 in the presence of an ActRIIB and / or ActRIIA ligand; and (d) a K of ≦1 nM and ≧1 pM. D (e.g., as determined by BIACORE® analysis) binds to ActRIIB and / or ActRIIA. In some embodiments, the ActRIIB and ActRIIA binding proteins have two, three, or four of the above characteristics. In some embodiments, the ActRIIB and ActRIIA binding proteins have at least two or at least three of the above characteristics.

[0244] In some aspects, the ActRII binding protein specifically binds ActRIIA and comprises a VH and a VL, wherein the VH sequence is identical to or has a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, less than 15, or 0 amino acid substitutions, deletions, and / or insertions from the reference VH sequence of SEQ ID NO: 125. The VL sequence is identical to or has a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, less than 15, or 0 amino acid substitutions, additions, and / or deletions from the reference VL sequence of SEQ ID NO: 132. In a further aspect, the ActRIIA binding protein has at least one characteristic selected from the group consisting of: (a) competing with an ActRIIA ligand (e.g., activin A, activin B, GDF1, GDF3, or Nodal); (b) reducing phosphorylation of Smads (e.g., Smad2 and / or Smad3) in cells expressing ActRIIA in the presence of an ActRIIA ligand (e.g., activin A); (c) reducing phosphorylation of ALK4 and / or ALK7 in cells expressing ActRIIA and ALK4 and / or ALK7 in the presence of an ActRIIA ligand; and (d) a K of ≦1 nM and ≧1 pM. D (e.g., as determined by BIACORE® analysis) binds to ActRIIA. In some embodiments, the ActRIIA binding protein has two, three, or four of the above characteristics. In some embodiments, the ActRIIA binding protein has at least two or at least three of the above characteristics.

[0245] In some embodiments, the ActRII binding protein is an antibody that specifically binds to ActRII. In some embodiments, the anti-ActRII specifically binds to ActRIIB and / or ActRIIA. In some embodiments, the anti-ActRII antibody is a murine antibody, a humanized antibody, a chimeric antibody, a monoclonal antibody, a polyclonal antibody, a recombinant antibody, a multispecific antibody, or any combination thereof. In some embodiments, the anti-ActRII antibody is an Fv fragment, a Fab fragment, a F(ab')2 fragment, a Fab' fragment, a dsFv fragment, an scFv fragment, or an sc(Fv)2 fragment.

[0246] In some embodiments, the ActRII binding protein specifically binds to ActRII (e.g., ActRIIA and / or ActRIIB) and blocks the activity of an ActRII-ligand (e.g., GDF8 (myostatin) and / or activin). In some embodiments, the ActRII binding protein specifically binds to ActRII (e.g., reduces the inhibition of muscle formation or increased adipogenesis associated with the activity of an ActRII ligand (e.g., GDF8 (myostatin) and / or activin)). In some embodiments, the ActRII binding protein specifically binds to ActRII and treats or ameliorate one or more conditions associated with a muscle disorder or a metabolic disorder. In some embodiments, the muscle disorder is muscle wasting due to disease or disuse. In some embodiments, the metabolic disorder is diabetes, obesity, hyperglycemia, or bone loss.

[0247] In certain aspects, the ActRIIB binding protein (e.g., an anti-ActRIIB antibody or an anti-ActRIIB and ActRIIA antibody) inhibits or reduces the binding of ActRIIB by GDF8 (myostatin) or GDF8-mediated ActRIIB Smad signaling. In another aspect, the ActRIIB binding protein reduces the inhibition of muscle formation or the increase in adipogenesis. In some aspects, the ActRIIB binding protein binds to ActRIIB and inhibits or reduces one or more conditions associated with a muscle disorder or a metabolic disorder. In some aspects, the muscle disorder is muscle wasting due to disease or disuse. In some aspects, the metabolic disorder is diabetes, obesity, hyperglycemia, or bone loss, and increases muscle mass or strength in a subject.

[0248] In certain aspects, blocking ActRII (e.g., ActRIIB and / or ActRIIA) activity by the ActRII binding proteins described herein (e.g., anti-ActRIIB antibodies and anti-ActRIIA antibodies) inhibits or reduces one or more conditions associated with muscle disorders, e.g., muscle wasting. In further aspects, blocking ActRII inhibits or reduces one or more conditions associated with muscle wasting due to disease or disuse. In certain aspects, the ActRII binding proteins (e.g., anti-ActRIIB antibodies or anti-ActRIIB and ActRIIA antibodies) inhibit or reduce binding of ActRIIB by GDF8. In another aspect, the ActRIIB binding proteins inhibit or reduce inhibition of muscle differentiation by the Smad-dependent pathway.

[0249] In some embodiments, the ActRII binding protein specifically binds to ActRIIB and blocks ActRIIB ligand-mediated activity. Some ActRIIB ligands, such as GDF-8, are known to be negative regulators of skeletal muscle tissue, and myostatin signaling is known to lead to muscle mass. ActRIIB ligand-mediated signaling can also regulate the production of muscle-specific enzymes (e.g., creatine kinase), stimulate myoblast proliferation, and regulate the differentiation of preadipocytes into adipocytes. Increased myostatin activity is associated with muscle wasting disorders, muscle weakness due to inactivity, and metabolic disorders such as diabetes, obesity, hyperglycemia, and bone loss. Increased ActRIIB ligand-mediated activity is also associated with age-related increases in fat / muscle ratio and age-related muscle atrophy. In some embodiments, the ActRII binding protein specifically binds to ActRIIB and reduces the inhibition of muscle formation or increased adipogenesis associated with the activity of some ActRIIB ligands. In some embodiments, ActRII binding protein specifically binds to ActRIIB and treats or improves one or more conditions associated with muscle disorder or metabolic disorder.In some embodiments, muscle disorder is muscle wasting due to disease or disuse.In some embodiments, metabolic disorder is diabetes, obesity, hyperglycemia or bone loss.ActRIIB ligand-mediated activity can be determined by art-recognized methods, for example, those described herein.

[0250] In certain aspects, blockage of ActRII (e.g., ActRIIB and / or ActRIIA) activity by the ActRII binding proteins described herein (e.g., anti-ActRIIB antibodies and anti-ActRIIA antibodies) reduces one or more conditions associated with fibrosis. In certain aspects, the ActRIIB binding proteins inhibit or reduce ActRIIB-mediated development of fibrotic lesions, reduction in weight loss or other clinical symptoms, and / or changes in expression of biomolecules (e.g., mRNA or protein expression) associated with the development of a fibrotic condition. In certain aspects, the ActRIIA binding proteins inhibit or reduce ActRIIA-mediated development of fibrotic lesions, reduction in weight loss or other clinical symptoms, and / or changes in expression of biomolecules (e.g., mRNA or protein expression) associated with the development of a fibrotic condition.

[0251] As described above, ActRII-binding proteins (e.g., full-length ActRIIB antibodies and ActRII-binding antibody fragments, and variants and derivatives thereof) containing VH and / or VL amino acid sequences that bind to ActRII may have at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity with the sequences set forth herein. In some aspects, the VH and / or VL amino acid sequence(s) that bind to ActRII contain 8, 7, 6, 5, 4, 3, 2, or 1 amino acid additions, substitutions (e.g., conservative substitutions), or deletions compared to the sequences set forth herein. In further aspects, the VH and / or VL amino acid sequences that bind to ActRII contain 1, 2, 3, 4, 5, or more amino acid additions, substitutions (e.g., conservative substitutions), or deletions compared to the sequences set forth herein. Anti-ActRII antibodies containing VH and VL regions having a particular percent similarity to a VH or VL region or having one or more substitutions, deletions and / or insertions (e.g., conservative substitutions) can be obtained by mutagenesis (e.g., site-directed or PCR-mediated mutagenesis) of nucleic acid molecules encoding the VH and / or VL regions described herein, followed by testing the encoded modified antibodies for binding to ActRII and, if necessary, for retained function using functional assays described herein or assays known in the art that can be routinely modified to test for retained function.

[0252] The affinity or avidity of an ActRII-binding protein, such as an anti-ActRIIB antibody (e.g., a full-length ActRIIB antibody and an ActRII-binding antibody fragment, as well as variants and derivatives thereof), for hActRIIB or murActRIIB can be experimentally determined using any suitable method known in the art, such as flow cytometry, enzyme-linked immunosorbent assay (ELISA), or radioimmunoassay (RIA), or kinetics (e.g., BIACORE® or KINEXA® analysis). Direct binding assays and competitive binding assay formats can be readily employed. (See, e.g., Berzofsky et al., "Antibody-Antigen Interactions," In Fundamental Immunology, Paul, WE, Ed., Raven Press: New York, NY (1984); Kuby, Immunology, WH Freeman and Company: New York, NY (1992); and the methods described herein.) The measured affinity for a particular antibody-antigen interaction may vary when measured under different conditions (e.g., salt concentration, pH, temperature). Therefore, affinity and other ActRII binding parameters (e.g., K D or Kd, K on , K. off ) is measured with standard solutions of ActRII binding protein and ActRII, and the measurements are performed using standardized conditions and methods described herein or alternatively known in the art.

[0253] The present disclosure further provides ActRII binding proteins, such as anti-ActRIIB antibodies and / or anti-ActRIIA antibodies as described herein, wherein the ActRII binding proteins are conjugated to a heterologous agent. In certain embodiments, the heterologous agent is an antibacterial agent, a therapeutic agent, a prodrug, a peptide, a protein, an enzyme, a lipid, a biological response modifier, a pharmaceutical agent, a lymphokine, a heterologous antibody or antibody fragment, a detectable label, or polyethylene glycol (PEG). Heteroconjugate ActRII binding proteins are discussed in more detail elsewhere herein.

[0254] In certain embodiments, the ActRII binding protein is not an anti-ActRII antibody. Various methods for identifying and generating non-antibody polypeptides that bind to protein targets with high affinity are known in the art. See, for example, Skerra, Curr. Opin. Biotech. 18:295-304 (2007); Hosse et al., Protein Science 15:14-27 (2006); Gill et al., Curr. Opin. Biotechnol. 17:653-658 (2006); Nygren, FEBS J. 275:2668-2676 (2008); and Skerra, FEBS J. 275:2677-83 (2008) (each of which is incorporated herein by reference in its entirety). In some embodiments, phage display technology can be used to identify / generate ActRII binding proteins. In some embodiments, the ActRII binding protein comprises a protein scaffold based on a type selected from the group consisting of a VASP polypeptide, avian pancreatic polypeptide (aPP), tetranectin (based on CTLD3), affilin (based on γB-crystallin / ubiquitin), knottin, an SH3 domain, a PDZ domain, tendamistat, transferrin, ankyrin consensus repeat domains (e.g., DARPins), lipocalin protein folds (e.g., anticalins and duocalins), protein epitope mimics (PEMs), maxybodies / avimers, domain antibodies, fibronectin domains (e.g., 10Fn3; see, e.g., U.S. Patent Publication Nos. 2003 / 0170753 and 20090155275, each of which is incorporated herein by reference in its entirety), a domain of Protein A (e.g., an affibody), and thioredoxin.

[0255] In some aspects, the present disclosure provides ActRIIA binding proteins (e.g., anti-ActRIIA antibodies, e.g., full-length anti-ActRIIA antibodies, and ActRIIA-binding antibody fragments) that compete with the anti-ActRIIA antibodies provided herein for binding to ActRIIA. In some aspects, the present disclosure provides ActRIIA binding proteins that bind to the same epitope of ActRIIA as the ActRIIA binding proteins provided herein.

[0256] In some aspects, the present disclosure provides ActRIIB binding proteins (e.g., anti-ActRIIB antibodies, e.g., full-length anti-ActRIIB antibodies, and ActRIIB-binding antibody fragments) that compete with the anti-ActRIIB antibodies provided herein for binding to ActRIIB. In some aspects, the present disclosure provides ActRIIB binding proteins that bind to the same epitope of ActRIIB as the ActRIIB binding proteins provided herein. The ability of a test ActRII binding protein to inhibit the binding of a reference binding protein, such as an antibody comprising the VH sequence of SEQ ID NO: 40 and the VL sequence of SEQ ID NO: 9, or the VH sequence of SEQ ID NO: 119 and the VL sequence of SEQ ID NO: 91, to ActRIIB demonstrates that the test ActRII binding protein can compete with ActRIIB for binding to the reference antibody. Such an ActRIIB binding protein may, according to non-limiting theory, bind to the same or a related (e.g., structurally similar or spatially proximate) epitope on ActRIIB as the ActRIIB reference antibody with which it competes. In one aspect, the ActRIIB binding protein binds to the same epitope on ActRIIB as an antibody comprising the VH sequence of SEQ ID NO: 40 and the VL sequence of SEQ ID NO: 9.

[0257] ActRII receptors, e.g., ActRIIB and ActRIIA, are known to phosphorylate ActRI coreceptors (e.g., Alk4 and Alk7) and signal through phosphorylation of Smads (e.g., Smad2 and / or Smad3). In some embodiments, ActRII binding proteins (e.g., anti-ActRIIB antibodies and anti-ActRIIA antibodies) can reduce ActRII-mediated phosphorylation of their cognate ActRI receptors. In some embodiments, ActRIIB binding proteins (e.g., anti-ActRIIB antibodies) can reduce ActRIIB-mediated phosphorylation of ALK4 and / or ALK7. In some embodiments, ActRIIA binding proteins (e.g., anti-ActRIIA antibodies) can reduce ActRIIA-mediated phosphorylation of ALK4 and / or ALK7. In some embodiments, ActRII binding proteins can inhibit ActRII-mediated Smad (e.g., Smad2 and / or Smad3) phosphorylation in ActRII2-expressing cells. In some aspects, an ActRIIB binding protein (e.g., an anti-ActRIIB antibody) can reduce ActRIIB-mediated Smad (e.g., Smad2 and / or Smad3) phosphorylation in cells expressing ActRIIB. In some aspects, an ActRIIA binding protein (e.g., an anti-ActRIIA antibody) can reduce ActRIIA-mediated Smad (e.g., Smad2 and / or Smad3) phosphorylation in cells expressing ActRIIA. In some aspects, the cells expressing an ActRII receptor are human.

[0258] In some embodiments, the ActRII binding protein has at least one characteristic selected from the following: (a) competes with activin A for binding to ActRIIA and / or ActRIIB; (b) reduces phosphorylation of Smads (e.g., Smad2 and / or Smad3) in cells expressing ActRIIA and / or ActRIIB in the presence of an ActRIIA and / or ActRIIB ligand (e.g., activin A); (c) reduces phosphorylation of ALK4 and / or ALK7 in cells expressing ActRIIA and / or ActRIIB and ALK4 and / or ALK7 in the presence of an ActRIIB and / or ActRIIA ligand; and (d) a K of ≦1 nM and ≧1 pM as determined by BIACORE® or KINEXA®. D and binds to ActRIIA and / or ActRIIB.

[0259] In some embodiments, the ActRII binding protein (e.g., an anti-ActRII antibody) inhibits ActRII-mediated phosphorylation of an ActRI receptor (e.g., ALK4 and / or ALK7) or phosphorylation of Smads (e.g., Smad2 and / or Smad3) in cells expressing ActRII, as measured using a cell-based assay. In some embodiments, the ActRII binding protein has an IC of less than 500 pM, less than 350 pM, less than 250 pM, less than 150 pM, less than 100 pM, less than 75 pM, less than 60 pM, less than 50 pM, less than 40 pM, less than 30 pM, less than 20 pM, less than 15 pM, less than 10 pM, or less than 5 pM, as measured using a cell-based assay. 50 inhibits ActRII-mediated phosphorylation.

[0260] Preparation of ActRII-binding proteins In some aspects, the ActRII binding protein binds to the extracellular domain of ActRII (e.g., ActRIIB and ActRIIA). In further aspects, the ActRII binding protein is an anti-ActRIIA antibody and / or an anti-ActRIIB antibody, e.g., a full-length anti-ActRIIA antibody and a full-length anti-ActRIIB antibody and an ActRII-binding antibody fragment, and variants and derivatives thereof.

[0261] ActRII binding proteins can be readily prepared using known techniques. Monoclonal anti-ActRII (e.g., ActRIIB and ActRIIA) antibodies can be prepared using techniques known in the art, including the hybridoma method described in Kohler and Milstein, Nature 256:495-497 (1975), for example. Using the hybridoma method, mice, hamsters, or other suitable host animals are immunized as described above to induce lymphocyte production of antibodies that specifically bind to the immunizing antigen. Lymphocytes can also be immunized in vitro. After immunization, lymphocytes are isolated and fused with a suitable myeloma cell line to form hybridoma cells, which can then be selected from unfused lymphocytes and myeloma cells. Hybridomas producing monoclonal antibodies specifically directed against ActRII, such as hActRIIB and hActRIIA, as determined by immunoprecipitation, immunoblotting, or in vitro binding assays (e.g., radioimmunoassay (RIA); enzyme-linked immunosorbent assay (ELISA)), can be expanded in vitro in culture or in vivo as ascites tumors in animals using standard methods (see, e.g., Goding, Monoclonal Antibodies: Principles and Practice, Academic Press, 1986). Monoclonal antibodies can then be purified from the culture medium or ascites fluid as described above for polyclonal antibodies.

[0262] The provided monoclonal antibodies can also be produced using recombinant DNA methods, as described in U.S. Patent No. 4,816,567. Polynucleotides encoding the monoclonal antibodies are isolated from mature B cells or hybridoma cells, for example, by RT-PCR using oligonucleotide primers that specifically amplify genes encoding the antibody heavy and light chains, and their sequences are determined using known procedures. The isolated polynucleotides encoding the heavy and light chains are then cloned into suitable expression vectors that, when transfected into host cells that do not otherwise produce immunoglobulin protein, such as E. coli cells, simian COS cells, Chinese hamster ovary (CHO) cells, Per.C6 cells, or myeloma cells, result in the production of the monoclonal antibody by the host cells. Recombinant anti-ActRII monoclonal antibodies can also be easily isolated from phage display libraries expressing the CDRs of the desired species using known techniques (see, e.g., McCafferty et al., Nature 348:552-554 (1990); Clackson et al., Nature 352:624-628 (1991); and Marks et al., J. Mol. Biol. 222:581-597 (1991)).

[0263] Anti-ActRII antibodies can be humanized, resurfaced, and engineered, as needed, to exhibit high affinity for ActRII antigens (e.g., ActRIIB and ActRIIA) and other favorable biological properties. For example, humanized (or human) anti-ActRII antibodies can be readily designed and prepared using publicly available three-dimensional immunoglobulin modeling and known procedures for selecting framework (FW) residues, consensus sequences, and germline sequences to provide desired antibody properties, such as increased affinity for ActRII.

[0264] Affinity maturation and chain shuffling strategies are known in the art and can be utilized to generate high-affinity anti-ActRII (e.g., anti-ActRIIA and / or anti-ActRIIB) antibodies, and derivatives and variants of the ActRII binding proteins disclosed herein. See, e.g., Marks et al., Bio / Technology 10:779-783 (1992), incorporated herein by reference in its entirety. A further strategy for generating high-affinity anti-ActRII (e.g., anti-ActRIIA and / or anti-ActRIIB) antibodies, and derivatives and variants of the ActRII binding proteins disclosed herein uses random mutagenesis of one or more selected VH and / or VL genes to generate mutations within the entire variable domain, generating novel VH or VL regions bearing CDR-derived sequences of the present disclosure. Such a technique using error-prone PCR is described in Gram et al. (PNAS USA 89:3576-3580 (1992)). In some embodiments, one or two amino acid substitutions are made within a set of VH CDRs and / or VL CDRs. A further strategy used directed mutagenesis of the VH or VL gene CDR regions encoding the anti-ActRII antibodies disclosed herein. Examples of such techniques are described in Barbas et al. (PNAS USA 91:3809-3813 (1994)) and Schier et al. (J. Mol. Biol. 263:551-567 (1996)).

[0265] Humanization, resurfacing, or genetic engineering of the anti-ActRII antibodies of the present disclosure may be performed using techniques similar to those described in Jones et al., Nature 321:522 (1986); Riechmann et al., Nature 332:323 (1988); Verhoeyen et al., Science 239:1534 (1988)), Sims et al., J. Immunol. 151:2296 (1993); Chothia et al., J. Mol. Biol. 196:901 (1987), Carter et al., PNAS USA 89:4285 (1992); Presta et al. al., J. Immunol. 151:2623 (1993), U.S. Patent No. 5,639,641, U.S. Patent No. 5,723,323; U.S. Patent No. 5,976,862; No. 5,824,514; No. 5,817,483; No. 5,814,476; No. 5,763,192; No. 5,723,323; No. 5,766, Nos. 886; 5,714,352; 6,204,023; 6,180,370; 5,693,762; 5,530,101; 5,585,089; 5,225,539; 4,816,567; 7,557,189; 7,538,195; and 7,342, 110; International Application Nos. PCT / US98 / 16280; PCT / US96 / 18978; PCT / US91 / 09630; PCT / US91 / 05939; PCT / US94 / 01234; PCT / GB89 / 01334; PCT / GB91 / 01134; PCT / GB92 / 01755; International Application Publication Nos. WO90 / 14443; WO90 / 14424; WO90 / 14430; and European Patent Publication No. EP229246; each of which is incorporated herein by reference in its entirety. Similarly, known assays are available to easily select ActRII antibodies that exhibit desirable properties (e.g., assays to determine binding affinity to ActRII; cross-blocking assays such as the BIACORE®-based human ActRII binding protein competitive binding assay described herein).

[0266] Methods for engineering, humanizing, or resurfacing non-human or human antibodies are also available and known in the art. Humanized, resurfaced, or similarly engineered antibodies can have one or more amino acid residues derived from non-human sources (e.g., mouse, rat, rabbit, non-human primate, or other mammalian species). These non-human amino acid residues are often referred to as "import" residues and are typically replaced by residues taken from the "import" variable, constant, or other domains of a known human sequence. Such imported sequences can be used to reduce immunogenicity or to reduce, enhance, or improve binding, affinity, on-rate, off-rate, avidity, specificity, half-life, or any other suitable property, as known in the art. Preferably, some or all of the non-human or human CDR sequences are maintained, but the non-human sequences in the variable and constant regions can be replaced with human or other amino acids.

[0267] Nucleic acid(s) encoding an ActRII binding protein, e.g., a full-length anti-ActRIIA or anti-ActRIIB antibody, can be further modified in several different ways using recombinant DNA technology to generate alternative antibodies. In some embodiments, the nucleic acid(s) encoding the light and heavy chain constant domains of, e.g., a murine monoclonal antibody, can be (a) substituted with the coding regions of, e.g., a human antibody to generate a chimeric antibody, or (b) substituted with non-immunoglobulin encoding nucleic acid(s) to generate a fusion antibody. In some embodiments, the constant region(s) are truncated or removed to generate a desired antibody fragment of the monoclonal antibody. Site-directed or high-density mutagenesis of the variable region-encoding sequence can be used to optimize the specificity, affinity, etc. of the monoclonal antibody.

[0268] Human anti-ActRII antibodies can be prepared directly using various techniques known in the art (see, for example, Cole et al., Monoclonal Antibodies and Cancer Therapy, Alan R. Liss, p. 77 (1985); Boemer et al., J. Immunol. 147(1):86-95 (1991); and U.S. Patent No. 5,750,373). Similarly, human anti-ActRII antibodies can be readily obtained from immortalized human B lymphocytes that produce antibodies against ActRII (e.g., ActRIIB and ActRIIA) immunized in vitro or isolated from immunized individuals.

[0269] Human anti-ActRII antibodies can also be selected from phage libraries expressing human antibodies, as described, for example, in Vaughan et al., Nat. Biotech. 14:309-314 (1996), Sheets et al., PNAS 95:6157-6162 (1998), Hoogenboom and Winter, J. Mol. Biol. 227:381 (1991), and Marks et al., J. Mol. Biol. 222:581 (1991). Techniques for generating and screening antibody phage libraries are also described in U.S. Pat. Nos. 5,969,108, 6,172,197, 5,885,793, 6,521,404; 6,544,731; 6,555,313; 6,582,915; 6,593,081; 6,300,064; 6,653,068; 6,706,484; and 7,264,963; and Rothe et al., J. Mol. Biol. 376(4):1182-1200 (2008), each of which is incorporated by reference in its entirety.

[0270] Human anti-ActRII antibodies can also be produced in transgenic mice containing human immunoglobulin loci that, upon immunization, can produce human antibodies in the absence of endogenous immunoglobulin production. This approach is described, for example, in U.S. Patent Nos. 5,545,807; 5,545,806; 5,569,825; 5,625,126; 5,633,425; and 5,661,016.

[0271] Human anti-ActRII antibodies can also be selected and / or isolated from yeast-based antibody display libraries, such as those disclosed in WO012 / 009568; WO09 / 036379; WO10 / 105256; WO03 / 074679, and U.S. Application Publication No. US2002 / 0177170 (the contents of each of which are incorporated by reference in their entirety). Such libraries are designed in silico to reflect the diversity provided by the human pre-immune repertoire.

[0272] Alternatively, anti-ActRII antibodies may be selected from yeast display antibody libraries (see, for example, Blaise et al., Gene 342(2):211-218 (2004); Boder et al., Nat Biotechnol. 15(6):553-557 (1997); Kuroda et al., Biotechnol. Lett. 33(1):1-9 (2011). Review; Lauer et al., J. Pharm. Sci. 101(1):102-15 (2012); Orcutt KD and Wittrup KD Antibody Engineering, Yeast Display and Selection (2010), 207-233; Rakestraw et al., Protein See Eng. Des. Sel. 24(6):525-30 (2011); and U.S. Patent Nos. 6,423,538; 6,696,251; and 6,699,658.

[0273] Various techniques for producing antigen-binding antibody fragments are known. Traditionally, these fragments are derived from proteolytic digestion of intact antibodies (see, e.g., Morimoto et al., J. Biochem. Biophys. Meth. 24:107-117 (1993); and Brennan et al., Science 229:81 (1985)). In certain embodiments, ActRII-binding antibody fragments are recombinantly produced. Fab, Fv, and scFv antibody fragments can all be expressed and secreted in E. coli or other host cells, allowing for the large-scale production of these fragments. Such ActRII-binding antibody fragments can also be isolated from the aforementioned antibody phage libraries. In some embodiments, the ActRII-binding antibody fragment is a linear antibody, as described in U.S. Pat. No. 5,641,870. Other techniques for producing antigen-binding antibody fragments are known in the art.

[0274] Known techniques can be readily adapted to ...

Claims

1. a CDR set comprising: VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2, and VL-CDR3; The CDRs are (a) (i) a VH sequence of SEQ ID NO: 165, and (ii) the VL sequence of SEQ ID NO: 172, and the protein binds to activin receptor type IIB (ActRIIB); (b) (i) a VH sequence of SEQ ID NO: 2, 16, 22, 28, 34, or 40; and (ii) the VL sequence of SEQ ID NO: 9, and the protein binds to ActRIIB; (c) (i) a VH sequence of SEQ ID NO: 63 or 77, and (ii) a VL having the amino acid sequence of SEQ ID NO: 70; and the protein binds to ActRIIB; (d) (i) a VH sequence of SEQ ID NO: 45 or 57, and (ii) a VL sequence of SEQ ID NO: 50, and the protein binds to ActRIIB; (e) (i) the VH sequence of SEQ ID NO: 144, and (ii) the VL sequence of SEQ ID NO: 151, and the protein binds to ActRIIB; (f) (i) a VH sequence of SEQ ID NO: 84, 98, 105, 112, or 119; and (ii) the VL sequence of SEQ ID NO: 91, and The protein binds to ActRIIB and activin receptor type IIA (ActRIIA); and (g) (i) the VH sequence of SEQ ID NO: 125, and (ii) the VL sequence of SEQ ID NO: 132, and the protein binds to ActRIIA; An isolated activin receptor type II (ActRII) binding protein present in a heavy chain variable region (VH) and light chain variable region (VL) pair selected from the group consisting of:

2. a CDR set comprising: VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2, and VL-CDR3; The CDR set comprises: (a)(i) VH-CDR1 has the amino acid sequence of SEQ ID NO: 166; (ii) VH-CDR2 has the amino acid sequence of SEQ ID NO: 167; (iii) VH-CDR3 has the amino acid sequence of SEQ ID NO: 168; (iv) VL-CDR1 has the amino acid sequence of SEQ ID NO: 173; (v) VL-CDR2 has the amino acid sequence of SEQ ID NO: 174; and (vi) VL-CDR3 has the amino acid sequence of SEQ ID NO: 175; and the protein binds to ActRIIB; (b)(i) VH-CDR1 has the amino acid sequence of SEQ ID NO: 3, 17, 23, 29, 35, or 41; (ii) VH-CDR2 has the amino acid sequence of SEQ ID NO: 4, 18, 24, 30, or 36; (iii) VH-CDR3 has the amino acid sequence of SEQ ID NO:5; (iv) VL-CDR1 has the amino acid sequence of SEQ ID NO: 10; (v) VL-CDR2 has the amino acid sequence of SEQ ID NO: 11; and (vi) VL-CDR3 has the amino acid sequence of SEQ ID NO: 12; and the protein binds to ActRIIB; (c)(i) VH-CDR1 has the amino acid sequence of SEQ ID NO: 64 or 78; (ii) VH-CDR2 has the amino acid sequence of SEQ ID NO: 65 or 79; (iii) VH-CDR3 has the amino acid sequence of SEQ ID NO: 66 or 80; (iv) VL-CDR1 has the amino acid sequence of SEQ ID NO: 71; (v) VL-CDR2 has the amino acid sequence of SEQ ID NO: 72; and (vi) VL-CDR3 has the amino acid sequence of SEQ ID NO: 73; and the protein binds to ActRIIB; (d)(i) VH-CDR1 has the amino acid sequence of SEQ ID NO: 3 or 58; (ii) VH-CDR2 has the amino acid sequence of SEQ ID NO: 4 or 59; (iii) VH-CDR3 has the amino acid sequence of SEQ ID NO: 46; (iv) VL-CDR1 has the amino acid sequence of SEQ ID NO: 51; (v) VL-CDR2 has the amino acid sequence of SEQ ID NO: 52; and (vi) VL-CDR3 has the amino acid sequence of SEQ ID NO: 53; and the protein binds to ActRIIB; (e)(i) VH-CDR1 has the amino acid sequence of SEQ ID NO: 145; (ii) VH-CDR2 has the amino acid sequence of SEQ ID NO: 146; (iii) VH-CDR3 has the amino acid sequence of SEQ ID NO: 147; (iv) VL-CDR1 has the amino acid sequence of SEQ ID NO: 152; (v) VL-CDR2 has the amino acid sequence of SEQ ID NO: 153; and (vi) VL-CDR3 has the amino acid sequence of SEQ ID NO: 154; and the protein binds to ActRIIB; (f)(i) VH-CDR1 has the amino acid sequence of SEQ ID NO: 85, 99, 106, or 113; (ii) VH-CDR2 has the amino acid sequence of SEQ ID NO: 86, 100, 107, 114, or 120; (iii) VH-CDR3 has the amino acid sequence of SEQ ID NO: 87, 101, 108, 115, or 121; (iv) VL-CDR1 has the amino acid sequence of SEQ ID NO: 92; (v) VL-CDR2 has the amino acid sequence of SEQ ID NO: 93; and (vi) VL-CDR3 has the amino acid sequence of SEQ ID NO: 94; and the protein binds to ActRIIB and ActRIIA; or (g)(i) VH-CDR1 has the amino acid sequence of SEQ ID NO: 126; (ii) VH-CDR2 has the amino acid sequence of SEQ ID NO: 127; (iii) VH-CDR3 has the amino acid sequence of SEQ ID NO: 128; (iv) VL-CDR1 has the amino acid sequence of SEQ ID NO: 133; (v) VL-CDR2 has the amino acid sequence of SEQ ID NO: 134; and (vi) VL-CDR3 has the amino acid sequence of SEQ ID NO: 135; and the protein binds to ActRIIA. An isolated ActRII binding protein having a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, less than 10, or 0 amino acid substitutions, deletions, and / or insertions from a reference set of CDRs.

3. (a)(i) VH-CDR1 has the amino acid sequence of SEQ ID NO: 166; (ii) VH-CDR2 has the amino acid sequence of SEQ ID NO: 167; (iii) VH-CDR3 has the amino acid sequence of SEQ ID NO: 168; (iv) VL-CDR1 has the amino acid sequence of SEQ ID NO: 173; (v) VL-CDR2 has the amino acid sequence of SEQ ID NO: 174; and (vi) VL-CDR3 has the amino acid sequence of SEQ ID NO: 175; and the protein binds to ActRIIB; (b)(i) VH-CDR1 has the amino acid sequence of SEQ ID NO: 3, 17, 23, 29, 35, or 41; (ii) VH-CDR2 has the amino acid sequence of SEQ ID NO: 4, 18, 24, 30, or 36; (iii) VH-CDR3 has the amino acid sequence of SEQ ID NO:5; (iv) VL-CDR1 has the amino acid sequence of SEQ ID NO: 10; (v) VL-CDR2 has the amino acid sequence of SEQ ID NO: 11; and (vi) VL-CDR3 has the amino acid sequence of SEQ ID NO: 12; and the protein binds to ActRIIB; (c)(i) VH-CDR1 has the amino acid sequence of SEQ ID NO: 64 or 78; (ii) VH-CDR2 has the amino acid sequence of SEQ ID NO: 65 or 79; (iii) VH-CDR3 has the amino acid sequence of SEQ ID NO: 66 or 80; (iv) VL-CDR1 has the amino acid sequence of SEQ ID NO: 71; (v) VL-CDR2 has the amino acid sequence of SEQ ID NO: 72; and (vi) VL-CDR3 has the amino acid sequence of SEQ ID NO: 73; and the protein binds to ActRIIB; (d)(i) VH-CDR1 has the amino acid sequence of SEQ ID NO: 3 or 58; (ii) VH-CDR2 has the amino acid sequence of SEQ ID NO: 4 or 59; (iii) VH-CDR3 has the amino acid sequence of SEQ ID NO: 46; (iv) VL-CDR1 has the amino acid sequence of SEQ ID NO: 51; (v) VL-CDR2 has the amino acid sequence of SEQ ID NO: 52; and (vi) VL-CDR3 has the amino acid sequence of SEQ ID NO: 53; and the protein binds to ActRIIB; (e)(i) VH-CDR1 has the amino acid sequence of SEQ ID NO: 145; (ii) VH-CDR2 has the amino acid sequence of SEQ ID NO: 146; (iii) VH-CDR3 has the amino acid sequence of SEQ ID NO: 147; (iv) VL-CDR1 has the amino acid sequence of SEQ ID NO: 152; (v) VL-CDR2 has the amino acid sequence of SEQ ID NO: 153; and (vi) VL-CDR3 has the amino acid sequence of SEQ ID NO: 154; and the protein binds to ActRIIB; (f)(i) VH-CDR1 has the amino acid sequence of SEQ ID NO: 85, 99, 106, or 113; (ii) VH-CDR2 has the amino acid sequence of SEQ ID NO: 86, 100, 107, 114, or 120; (iii) VH-CDR3 has the amino acid sequence of SEQ ID NO: 87, 101, 108, 115, or 121; (iv) VL-CDR1 has the amino acid sequence of SEQ ID NO: 92; (v) VL-CDR2 has the amino acid sequence of SEQ ID NO: 93; and (vi) VL-CDR3 has the amino acid sequence of SEQ ID NO: 94; and the protein binds to ActRIIB and ActRIIA; or (g)(i) VH-CDR1 has the amino acid sequence of SEQ ID NO: 126; (ii) VH-CDR2 has the amino acid sequence of SEQ ID NO: 127; (iii) VH-CDR3 has the amino acid sequence of SEQ ID NO: 128; (iv) VL-CDR1 has the amino acid sequence of SEQ ID NO: 133; (v) VL-CDR2 has the amino acid sequence of SEQ ID NO: 134; and (vi) VL-CDR3 has the amino acid sequence of SEQ ID NO: 135; and the protein binds to ActRIIA.

3. The isolated ActRII binding protein of claim 2, comprising a set of CDRs.

4. the CDR set (a)(i) VH-CDR1 has the amino acid sequence of SEQ ID NO: 166; (ii) VH-CDR2 has the amino acid sequence of SEQ ID NO: 167; (iii) VH-CDR3 has the amino acid sequence of SEQ ID NO: 168; (iv) VL-CDR1 has the amino acid sequence of SEQ ID NO: 173; (v) VL-CDR2 has the amino acid sequence of SEQ ID NO: 174; and (vi) VL-CDR3 has the amino acid sequence of SEQ ID NO: 175; and the protein binds to ActRIIB; (b)(i) VH-CDR1 has the amino acid sequence of SEQ ID NO:3; (ii) VH-CDR2 has the amino acid sequence of SEQ ID NO:4; (iii) VH-CDR3 has the amino acid sequence of SEQ ID NO:5; (iv) VL-CDR1 has the amino acid sequence of SEQ ID NO: 10; (v) VL-CDR2 has the amino acid sequence of SEQ ID NO: 11; and (vi) VL-CDR3 has the amino acid sequence of SEQ ID NO: 12; and the protein binds to ActRIIB; (c)(i) VH-CDR1 has the amino acid sequence of SEQ ID NO: 17; (ii) VH-CDR2 has the amino acid sequence of SEQ ID NO: 18; (iii) VH-CDR3 has the amino acid sequence of SEQ ID NO:5; (iv) VL-CDR1 has the amino acid sequence of SEQ ID NO: 10; (v) VL-CDR2 has the amino acid sequence of SEQ ID NO: 11; and (vi) VL-CDR3 has the amino acid sequence of SEQ ID NO: 12; and the protein binds to ActRIIB; (d)(i) VH-CDR1 has the amino acid sequence of SEQ ID NO: 23; (ii) VH-CDR2 has the amino acid sequence of SEQ ID NO: 24; (iii) VH-CDR3 has the amino acid sequence of SEQ ID NO:5; (iv) VL-CDR1 has the amino acid sequence of SEQ ID NO: 10; (v) VL-CDR2 has the amino acid sequence of SEQ ID NO: 11; and (vi) VL-CDR3 has the amino acid sequence of SEQ ID NO: 12; and the protein binds to ActRIIB; (e)(i) VH-CDR1 has the amino acid sequence of SEQ ID NO:29; (ii) VH-CDR2 has the amino acid sequence of SEQ ID NO: 30; (iii) VH-CDR3 has the amino acid sequence of SEQ ID NO:5; (iv) VL-CDR1 has the amino acid sequence of SEQ ID NO: 10; (v) VL-CDR2 has the amino acid sequence of SEQ ID NO: 11; and (vi) VL-CDR3 has the amino acid sequence of SEQ ID NO: 12; and the protein binds to ActRIIB; (f)(i) VH-CDR1 has the amino acid sequence of SEQ ID NO: 35; (ii) VH-CDR2 has the amino acid sequence of SEQ ID NO: 36; (iii) VH-CDR3 has the amino acid sequence of SEQ ID NO:5; (iv) VL-CDR1 has the amino acid sequence of SEQ ID NO: 10; (v) VL-CDR2 has the amino acid sequence of SEQ ID NO: 11; and (vi) VL-CDR3 has the amino acid sequence of SEQ ID NO: 12; and the protein binds to ActRIIB; (g)(i) VH-CDR1 has the amino acid sequence of SEQ ID NO: 41; (ii) VH-CDR2 has the amino acid sequence of SEQ ID NO: 18; (iii) VH-CDR3 has the amino acid sequence of SEQ ID NO:5; (iv) VL-CDR1 has the amino acid sequence of SEQ ID NO: 10; (v) VL-CDR2 has the amino acid sequence of SEQ ID NO: 11; and (vi) VL-CDR3 has the amino acid sequence of SEQ ID NO: 12; and the protein binds to ActRIIB; (h)(i) VH-CDR1 has the amino acid sequence of SEQ ID NO: 64; (ii) VH-CDR2 has the amino acid sequence of SEQ ID NO: 65; (iii) VH-CDR3 has the amino acid sequence of SEQ ID NO: 66; (iv) VL-CDR1 has the amino acid sequence of SEQ ID NO: 71; (v) VL-CDR2 has the amino acid sequence of SEQ ID NO: 72; and (vi) VL-CDR3 has the amino acid sequence of SEQ ID NO: 73; and the protein binds to ActRIIB; (i) (i) VH-CDR1 has the amino acid sequence of SEQ ID NO: 78; (ii) VH-CDR2 has the amino acid sequence of SEQ ID NO: 79; (iii) VH-CDR3 has the amino acid sequence of SEQ ID NO: 80; (iv) VL-CDR1 has the amino acid sequence of SEQ ID NO: 71; (v) VL-CDR2 has the amino acid sequence of SEQ ID NO: 72; and (vi) VL-CDR3 has the amino acid sequence of SEQ ID NO: 73; and the protein binds to ActRIIB; (j)(i) VH-CDR1 has the amino acid sequence of SEQ ID NO:3; (ii) VH-CDR2 has the amino acid sequence of SEQ ID NO:4; (iii) VH-CDR3 has the amino acid sequence of SEQ ID NO: 46; (iv) VL-CDR1 has the amino acid sequence of SEQ ID NO: 51; (v) VL-CDR2 has the amino acid sequence of SEQ ID NO: 52; and (vi) VL-CDR3 has the amino acid sequence of SEQ ID NO: 53; and the protein binds to ActRIIB; (k)(i) VH-CDR1 has the amino acid sequence of SEQ ID NO: 58; (ii) VH-CDR2 has the amino acid sequence of SEQ ID NO: 59; (iii) VH-CDR3 has the amino acid sequence of SEQ ID NO: 46; (iv) VL-CDR1 has the amino acid sequence of SEQ ID NO: 51; (v) VL-CDR2 has the amino acid sequence of SEQ ID NO: 52; and (vi) VL-CDR3 has the amino acid sequence of SEQ ID NO: 53; and the protein binds to ActRIIB; (l)(i) VH-CDR1 has the amino acid sequence of SEQ ID NO: 145; (ii) VH-CDR2 has the amino acid sequence of SEQ ID NO: 146; (iii) VH-CDR3 has the amino acid sequence of SEQ ID NO: 147; (iv) VL-CDR1 has the amino acid sequence of SEQ ID NO: 152; (v) VL-CDR2 has the amino acid sequence of SEQ ID NO: 153; and (vi) VL-CDR3 has the amino acid sequence of SEQ ID NO: 154; and the protein binds to ActRIIB; (m)(i) VH-CDR1 has the amino acid sequence of SEQ ID NO: 85; (ii) VH-CDR2 has the amino acid sequence of SEQ ID NO: 86; (iii) VH-CDR3 has the amino acid sequence of SEQ ID NO: 87; (iv) VL-CDR1 has the amino acid sequence of SEQ ID NO: 92; (v) VL-CDR2 has the amino acid sequence of SEQ ID NO: 93; and (vi) VL-CDR3 has the amino acid sequence of SEQ ID NO: 94; and the protein binds to ActRIIB and ActRIIA; (n)(i) VH-CDR1 has the amino acid sequence of SEQ ID NO: 99; (ii) VH-CDR2 has the amino acid sequence of SEQ ID NO: 100; (iii) VH-CDR3 has the amino acid sequence of SEQ ID NO: 101; (iv) VL-CDR1 has the amino acid sequence of SEQ ID NO: 92; (v) VL-CDR2 has the amino acid sequence of SEQ ID NO: 93; and (vi) VL-CDR3 has the amino acid sequence of SEQ ID NO: 94; and the protein binds to ActRIIB and ActRIIA; (o)(i) VH-CDR1 has the amino acid sequence of SEQ ID NO: 106; (ii) VH-CDR2 has the amino acid sequence of SEQ ID NO: 107; (iii) VH-CDR3 has the amino acid sequence of SEQ ID NO: 108; (iv) VL-CDR1 has the amino acid sequence of SEQ ID NO: 92; (v) VL-CDR2 has the amino acid sequence of SEQ ID NO: 93; and (vi) VL-CDR3 has the amino acid sequence of SEQ ID NO: 94; and the protein binds to ActRIIB and ActRIIA; (p)(i) VH-CDR1 has the amino acid sequence of SEQ ID NO: 113; (ii) VH-CDR2 has the amino acid sequence of SEQ ID NO: 114; (iii) VH-CDR3 has the amino acid sequence of SEQ ID NO: 115; (iv) VL-CDR1 has the amino acid sequence of SEQ ID NO: 92; (v) VL-CDR2 has the amino acid sequence of SEQ ID NO: 93; and (vi) VL-CDR3 has the amino acid sequence of SEQ ID NO: 94; and the protein binds to ActRIIB and ActRIIA; (q)(i) VH-CDR1 has the amino acid sequence of SEQ ID NO: 113; (ii) VH-CDR2 has the amino acid sequence of SEQ ID NO: 120; (iii) VH-CDR3 has the amino acid sequence of SEQ ID NO: 121; (iv) VL-CDR1 has the amino acid sequence of SEQ ID NO: 92; (v) VL-CDR2 has the amino acid sequence of SEQ ID NO: 93; and (vi) VL-CDR3 has the amino acid sequence of SEQ ID NO: 94; and the protein binds to ActRIIB and ActRIIA; or (r)(i) VH-CDR1 has the amino acid sequence of SEQ ID NO: 126; (ii) VH-CDR2 has the amino acid sequence of SEQ ID NO: 127; (iii) VH-CDR3 has the amino acid sequence of SEQ ID NO: 128; (iv) VL-CDR1 has the amino acid sequence of SEQ ID NO: 133; (v) VL-CDR2 has the amino acid sequence of SEQ ID NO: 134; and (vi) VL-CDR3 has the amino acid sequence of SEQ ID NO: 135; and the protein binds to ActRIIA.

3. The ActRII binding protein of claim 2, having a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, less than 10, or 0 amino acid substitutions, deletions, and / or insertions from the reference set of CDRs.

5. (a)(i) VH-CDR1 has the amino acid sequence of SEQ ID NO: 166; (ii) VH-CDR2 has the amino acid sequence of SEQ ID NO: 167; (iii) VH-CDR3 has the amino acid sequence of SEQ ID NO: 168; (iv) VL-CDR1 has the amino acid sequence of SEQ ID NO: 173; (v) VL-CDR2 has the amino acid sequence of SEQ ID NO: 174; and (vi) VL-CDR3 has the amino acid sequence of SEQ ID NO: 175; and the protein binds to ActRIIB; (b)(i) VH-CDR1 has the amino acid sequence of SEQ ID NO:3; (ii) VH-CDR2 has the amino acid sequence of SEQ ID NO:4; (iii) VH-CDR3 has the amino acid sequence of SEQ ID NO:5; (iv) VL-CDR1 has the amino acid sequence of SEQ ID NO: 10; (v) VL-CDR2 has the amino acid sequence of SEQ ID NO: 11; and (vi) VL-CDR3 has the amino acid sequence of SEQ ID NO: 12; and the protein binds to ActRIIB; (b)(i) VH-CDR1 has the amino acid sequence of SEQ ID NO: 17; (ii) VH-CDR2 has the amino acid sequence of SEQ ID NO: 18; (iii) VH-CDR3 has the amino acid sequence of SEQ ID NO:5; (iv) VL-CDR1 has the amino acid sequence of SEQ ID NO: 10; (v) VL-CDR2 has the amino acid sequence of SEQ ID NO: 11; and (vi) VL-CDR3 has the amino acid sequence of SEQ ID NO: 12; and the protein binds to ActRIIB; (c)(i) VH-CDR1 has the amino acid sequence of SEQ ID NO: 23; (ii) VH-CDR2 has the amino acid sequence of SEQ ID NO: 24; (iii) VH-CDR3 has the amino acid sequence of SEQ ID NO:5; (iv) VL-CDR1 has the amino acid sequence of SEQ ID NO: 10; (v) VL-CDR2 has the amino acid sequence of SEQ ID NO: 11; and (vi) VL-CDR3 has the amino acid sequence of SEQ ID NO: 12; and the protein binds to ActRIIB; (d)(i) VH-CDR1 has the amino acid sequence of SEQ ID NO:29; (ii) VH-CDR2 has the amino acid sequence of SEQ ID NO: 30; (iii) VH-CDR3 has the amino acid sequence of SEQ ID NO:5; (iv) VL-CDR1 has the amino acid sequence of SEQ ID NO: 10; (v) VL-CDR2 has the amino acid sequence of SEQ ID NO: 11; and (vi) VL-CDR3 has the amino acid sequence of SEQ ID NO: 12; and the protein binds to ActRIIB; (e)(i) VH-CDR1 has the amino acid sequence of SEQ ID NO: 35; (ii) VH-CDR2 has the amino acid sequence of SEQ ID NO: 36; (iii) VH-CDR3 has the amino acid sequence of SEQ ID NO:5; (iv) VL-CDR1 has the amino acid sequence of SEQ ID NO: 10; (v) VL-CDR2 has the amino acid sequence of SEQ ID NO: 11; and (vi) VL-CDR3 has the amino acid sequence of SEQ ID NO: 12; and the protein binds to ActRIIB; (f)(i) VH-CDR1 has the amino acid sequence of SEQ ID NO: 41; (ii) VH-CDR2 has the amino acid sequence of SEQ ID NO: 18; (iii) VH-CDR3 has the amino acid sequence of SEQ ID NO:5; (iv) VL-CDR1 has the amino acid sequence of SEQ ID NO: 10; (v) VL-CDR2 has the amino acid sequence of SEQ ID NO: 11; and (vi) VL-CDR3 has the amino acid sequence of SEQ ID NO: 12; and the protein binds to ActRIIB; (g)(i) VH-CDR1 has the amino acid sequence of SEQ ID NO: 64; (ii) VH-CDR2 has the amino acid sequence of SEQ ID NO: 65; (iii) VH-CDR3 has the amino acid sequence of SEQ ID NO: 66; (iv) VL-CDR1 has the amino acid sequence of SEQ ID NO: 71; (v) VL-CDR2 has the amino acid sequence of SEQ ID NO: 72; and (vi) VL-CDR3 has the amino acid sequence of SEQ ID NO: 73; and the protein binds to ActRIIB; (h)(i) VH-CDR1 has the amino acid sequence of SEQ ID NO: 78; (ii) VH-CDR2 has the amino acid sequence of SEQ ID NO: 79; (iii) VH-CDR3 has the amino acid sequence of SEQ ID NO: 80; (iv) VL-CDR1 has the amino acid sequence of SEQ ID NO: 71; (v) VL-CDR2 has the amino acid sequence of SEQ ID NO: 72; and (vi) VL-CDR3 has the amino acid sequence of SEQ ID NO: 73; and the protein binds to ActRIIB; (i) (i) VH-CDR1 has the amino acid sequence of SEQ ID NO: 3; (ii) VH-CDR2 has the amino acid sequence of SEQ ID NO:4; (iii) VH-CDR3 has the amino acid sequence of SEQ ID NO: 46; (iv) VL-CDR1 has the amino acid sequence of SEQ ID NO: 51; (v) VL-CDR2 has the amino acid sequence of SEQ ID NO: 52; and (vi) VL-CDR3 has the amino acid sequence of SEQ ID NO: 53; and the protein binds to ActRIIB; (j)(i) VH-CDR1 has the amino acid sequence of SEQ ID NO: 58; (ii) VH-CDR2 has the amino acid sequence of SEQ ID NO: 59; (iii) VH-CDR3 has the amino acid sequence of SEQ ID NO: 46; (iv) VL-CDR1 has the amino acid sequence of SEQ ID NO: 51; (v) VL-CDR2 has the amino acid sequence of SEQ ID NO: 52; and (vi) VL-CDR3 has the amino acid sequence of SEQ ID NO: 53; and the protein binds to ActRIIB; (k)(i) VH-CDR1 has the amino acid sequence of SEQ ID NO: 145; (ii) VH-CDR2 has the amino acid sequence of SEQ ID NO: 146; (iii) VH-CDR3 has the amino acid sequence of SEQ ID NO: 147; (iv) VL-CDR1 has the amino acid sequence of SEQ ID NO: 152; (v) VL-CDR2 has the amino acid sequence of SEQ ID NO: 153; and (vi) VL-CDR3 has the amino acid sequence of SEQ ID NO: 154; and the protein binds to ActRIIB; (l)(i) VH-CDR1 has the amino acid sequence of SEQ ID NO: 85; (ii) VH-CDR2 has the amino acid sequence of SEQ ID NO: 86; (iii) VH-CDR3 has the amino acid sequence of SEQ ID NO: 87; (iv) VL-CDR1 has the amino acid sequence of SEQ ID NO: 92; (v) VL-CDR2 has the amino acid sequence of SEQ ID NO: 93; and (vi) VL-CDR3 has the amino acid sequence of SEQ ID NO: 94; and the protein binds to ActRIIB and ActRIIA; (m)(i) VH-CDR1 has the amino acid sequence of SEQ ID NO: 99; (ii) VH-CDR2 has the amino acid sequence of SEQ ID NO: 100; (iii) VH-CDR3 has the amino acid sequence of SEQ ID NO: 101; (iv) VL-CDR1 has the amino acid sequence of SEQ ID NO: 92; (v) VL-CDR2 has the amino acid sequence of SEQ ID NO: 93; and (vi) VL-CDR3 has the amino acid sequence of SEQ ID NO: 94; and the protein binds to ActRIIB and ActRIIA; (n)(i) VH-CDR1 has the amino acid sequence of SEQ ID NO: 106; (ii) VH-CDR2 has the amino acid sequence of SEQ ID NO: 107; (iii) VH-CDR3 has the amino acid sequence of SEQ ID NO: 108; (iv) VL-CDR1 has the amino acid sequence of SEQ ID NO: 92; (v) VL-CDR2 has the amino acid sequence of SEQ ID NO: 93; and (vi) VL-CDR3 has the amino acid sequence of SEQ ID NO: 94; and the protein binds to ActRIIB and ActRIIA; (o)(i) VH-CDR1 has the amino acid sequence of SEQ ID NO: 113; (ii) VH-CDR2 has the amino acid sequence of SEQ ID NO: 114; (iii) VH-CDR3 has the amino acid sequence of SEQ ID NO: 115; (iv) VL-CDR1 has the amino acid sequence of SEQ ID NO: 92; (v) VL-CDR2 has the amino acid sequence of SEQ ID NO: 93; and (vi) VL-CDR3 has the amino acid sequence of SEQ ID NO: 94; and the protein binds to ActRIIB and ActRIIA; (p)(i) VH-CDR1 has the amino acid sequence of SEQ ID NO: 113; (ii) VH-CDR2 has the amino acid sequence of SEQ ID NO: 120; (iii) VH-CDR3 has the amino acid sequence of SEQ ID NO: 121; (iv) VL-CDR1 has the amino acid sequence of SEQ ID NO: 92; (v) VL-CDR2 has the amino acid sequence of SEQ ID NO: 93; and (vi) VL-CDR3 has the amino acid sequence of SEQ ID NO: 94; and the protein binds to ActRIIB and ActRIIA; or (q)(i) VH-CDR1 has the amino acid sequence of SEQ ID NO: 126; (ii) VH-CDR2 has the amino acid sequence of SEQ ID NO: 127; (iii) VH-CDR3 has the amino acid sequence of SEQ ID NO: 128; (iv) VL-CDR1 has the amino acid sequence of SEQ ID NO: 133; (v) VL-CDR2 has the amino acid sequence of SEQ ID NO: 134; and (vi) VL-CDR3 has the amino acid sequence of SEQ ID NO: 135; and the protein binds to ActRIIA.

5. The ActRII binding protein of claim 4, comprising a set of CDRs.

6. (a) (i) a VH having at least 90%, 95%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 165; and (ii) a VL having at least 90%, 95%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 172, and the protein binds ActRIIB; (b)(i) a VH having at least 90%, 95%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 2, 16, 22, 28, 34, or 40; and (ii) a VL having at least 90%, 95%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 9, and the protein binds ActRIIB; (c) (i) a VH having at least 90%, 95%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 45 or 57; and (ii) a VL having at least 90%, 95%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 50, and the protein binds ActRIIB; (d)(i) a VH having at least 90%, 95%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 63 or 77; and (ii) a VL having at least 90%, 95%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 70, and the protein binds ActRIIB; (e) (i) a VH having at least 90%, 95%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 144; and (ii) a VL having at least 90%, 95%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 151, and the protein binds ActRIIB; (f) (i) a VH having the amino acid sequence of SEQ ID NO: 84, 98, 105, 112, or 119; and (ii) a VL having the amino acid sequence of SEQ ID NO: 91; and The protein binds to ActRIIB and ActRIIA; and (g)(i) a VH having at least 90%, 95%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 125; and (ii) a VL having at least 90%, 95%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 132, and wherein the protein binds to ActRIIA.

7. the VH and VL pair (a) a VH sequence of SEQ ID NO: 165 and a VL sequence of SEQ ID NO: 172, wherein the protein binds to ActRIIB; (b) a VH sequence of SEQ ID NO: 2, 16, 22, 28, 34, or 40, and a VL sequence of SEQ ID NO: 9, wherein the protein binds ActRIIB; (c) a VH sequence of SEQ ID NO: 45 or 57 and a VL sequence of SEQ ID NO: 50, wherein the protein binds ActRIIB; (d) a VH sequence of SEQ ID NO: 63 or 77 and a VL sequence of SEQ ID NO: 70, wherein the protein binds to ActRIIB; (e) the VH sequence of SEQ ID NO: 144 and the VL sequence of SEQ ID NO: 151, wherein the protein binds to ActRIIB; (f) a VH sequence of SEQ ID NO: 84, 98, 105, 112, or 119 and a VL sequence of SEQ ID NO: 91, wherein the protein binds to ActRIIB and ActRIIA; and (g) a VH sequence of SEQ ID NO: 125 and a VL sequence of SEQ ID NO: 132, wherein the protein binds to ActRIIA.

7. The ActRII binding protein of claim 6, selected from the group consisting of:

8. the VH and VL pair (a) a VH having at least 90%, 95%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 165 and a VL having at least 90%, 95%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 172, and wherein the protein binds ActRIIB; (b) a VH having at least 90%, 95%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 2 and a VL having at least 90%, 95%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 9, wherein the protein binds ActRIIB; (c) a VH having at least 90%, 95%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 16, and a VL having at least 90%, 95%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 9, and wherein the protein binds ActRIIB; (d) a VH having at least 90%, 95%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 22 and a VL having at least 90%, 95%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 9, and wherein the protein binds ActRIIB; (e) a VH having at least 90%, 95%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 28 and a VL having at least 90%, 95%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 9, and wherein the protein binds ActRIIB; (f) a VH having at least 90%, 95%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 34, and a VL having at least 90%, 95%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 9, and wherein the protein binds ActRIIB; (g) a VH having at least 90%, 95%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 40, and a VL having at least 90%, 95%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 9, and wherein the protein binds ActRIIB; (h) a VH having at least 90%, 95%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 45, and a VL having at least 90%, 95%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 50, and wherein the protein binds ActRIIB; (i) a VH having at least 90%, 95%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 57, and a VL having at least 90%, 95%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 50, wherein the protein binds ActRIIB; (j) a VH having at least 90%, 95%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 63, and a VL having at least 90%, 95%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 70, and wherein the protein binds ActRIIB; (k) a VH having at least 90%, 95%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 77 and a VL having at least 90%, 95%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 70; and the protein binds ActRIIB; (l) a VH having at least 90%, 95%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 145 and a VL having at least 90%, 95%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 151; and the protein binds ActRIIB; (m) a VH having at least 90%, 95%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 84, and a VL having at least 90%, 95%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 91, and wherein the protein binds ActRIIB and ActRIIA; (n) a VH having at least 90%, 95%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 98, and a VH having at least 90%, 95%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 91, wherein the protein binds ActRIIB and ActRIIA; (o) a VH having at least 90%, 95%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 105, and a VL having at least 90%, 95%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 91, and wherein the protein binds ActRIIB and ActRIIA; (p) a VH having at least 90%, 95%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 112, and a VL having at least 90%, 95%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 91, and wherein the protein binds ActRIIB and ActRIIA; (q) a VH having at least 90%, 95%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 119, and a VL having at least 90%, 95%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 91, wherein the protein binds ActRIIB and ActRIIA; and (r) a VH having at least 90%, 95%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 125 and a VL having at least 90%, 95%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 132, and wherein the protein binds to ActRIIA.

8. The ActRII binding protein of claim 7 selected from the group consisting of:

9. the VH and VL pair (a) a VH sequence of SEQ ID NO: 165 and a VL sequence of SEQ ID NO: 172; (b) a VH sequence of SEQ ID NO: 2 and a VL sequence of SEQ ID NO: 9; (c) a VH sequence of SEQ ID NO: 16 and a VL sequence of SEQ ID NO: 9; (d) a VH sequence of SEQ ID NO: 22 and a VL sequence of SEQ ID NO: 9; (e) a VH sequence of SEQ ID NO: 28 and a VL sequence of SEQ ID NO: 9; (f) a VH sequence of SEQ ID NO: 34 and a VL sequence of SEQ ID NO: 9; (g) a VH sequence of SEQ ID NO: 40 and a VL sequence of SEQ ID NO: 9; (h) a VH sequence of SEQ ID NO: 45 and a VL sequence of SEQ ID NO: 50; (i) a VH sequence of SEQ ID NO: 57 and a VL sequence of SEQ ID NO: 50; (j) a VH sequence of SEQ ID NO: 63 and a VL sequence of SEQ ID NO: 70; (k) a VH sequence of SEQ ID NO: 77 and a VL sequence of SEQ ID NO: 70; (l) a VH sequence of SEQ ID NO: 144 and a VL sequence of SEQ ID NO: 151; (m) a VH sequence of SEQ ID NO: 84 and a VL sequence of SEQ ID NO: 91; (n) a VH sequence of SEQ ID NO: 98 and a VL sequence of SEQ ID NO: 91; (o) a VH sequence of SEQ ID NO: 105 and a VL sequence of SEQ ID NO: 91; (p) a VH sequence of SEQ ID NO: 112 and a VL sequence of SEQ ID NO: 91; (q) a VH sequence of SEQ ID NO: 119 and a VL sequence of SEQ ID NO: 91; and (r) a VH sequence of SEQ ID NO: 125 and a VL sequence of SEQ ID NO: 132 9. The ActRII binding protein of claim 8 selected from the group consisting of:

10. (a) (i) a VH sequence having a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, less than 15, or 0 amino acid substitutions, deletions, and / or insertions from a reference VH sequence selected from the group consisting of SEQ ID NO: 165; and (ii) a VL sequence having a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, less than 15, or 0 amino acid substitutions, deletions, and / or insertions from the reference VL sequence of SEQ ID NO: 172, and said protein binds ActRIIB; (b) (i) a VH sequence having a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, less than 15, or 0 amino acid substitutions, deletions, and / or insertions from a reference VH sequence selected from the group consisting of SEQ ID NOs: 2, 16, 22, 28, 34, or 40; and (ii) a VL sequence having a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, less than 15, or 0 amino acid substitutions, deletions, and / or insertions from a reference VL sequence of SEQ ID NO: 9, and said protein binds ActRIIB; (c) (i) a VH sequence having a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, less than 15, or 0 amino acid substitutions, deletions, and / or insertions from a reference VH sequence of SEQ ID NO: 45 or 57; and (ii) a VL sequence having a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, less than 15, or 0 amino acid substitutions, deletions, and / or insertions from a reference VL sequence of SEQ ID NO: 50, and said protein binds ActRIIB; (d) (i) a VH sequence having a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, less than 15, or 0 amino acid substitutions, deletions, and / or insertions from a reference VH sequence of SEQ ID NO: 63 or 77; and (ii) a VL sequence having a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, less than 15, or 0 amino acid substitutions, deletions, and / or insertions from a reference VL sequence of SEQ ID NO: 70, and said protein binds ActRIIB; (e) (i) a VH sequence having a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, less than 15, or 0 amino acid substitutions, deletions, and / or insertions from a reference VH sequence of SEQ ID NO: 144; and (ii) a VL sequence having a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, less than 15, or 0 amino acid substitutions, deletions, and / or insertions from a reference VL sequence of SEQ ID NO: 151, and said protein binds ActRIIB; (f) (i) a VH sequence having a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, less than 15, or 0 amino acid substitutions, deletions, and / or insertions from a reference VH sequence selected from the group consisting of SEQ ID NOs: 84, 98, 105, 112, or 119; and (ii) a VL sequence having a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, less than 15, or 0 amino acid substitutions, deletions, and / or insertions from the reference VL sequence of SEQ ID NO: 91, and said protein binds to ActRIIB and ActRIIA; and (g) (i) a VH sequence having a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, less than 15, or 0 amino acid substitutions, deletions, and / or insertions from a reference VH sequence of SEQ ID NO: 125; and (ii) a VL sequence having a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, less than 15, or 0 amino acid substitutions, deletions, and / or insertions from a reference VL of SEQ ID NO: 132, and said protein binds to ActRIIA. An ActRII binding protein comprising a VH and VL pair selected from the group consisting of:

11. (a) the VH sequence has a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, less than 15, or 0 amino acid substitutions, deletions, and / or insertions from a reference VH sequence of SEQ ID NO: 165; and the VL sequence has a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, less than 15, or 0 amino acid substitutions, deletions, and / or insertions from a reference VL sequence of SEQ ID NO: 172; and the protein binds to ActRIIB; (b) the VH sequence has a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15 or less, or 0 amino acid substitutions, deletions, and / or insertions from a reference VH sequence of SEQ ID NO: 2; and the VL sequence has a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15 or less, or 0 amino acid substitutions, deletions, and / or insertions from a reference VL sequence of SEQ ID NO: 9; and the protein binds to ActRIIB; (c) the VH sequence has a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, less than 15, or 0 amino acid substitutions, deletions, and / or insertions from a reference VH sequence of SEQ ID NO: 16; and the VL sequence has a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, less than 15, or 0 amino acid substitutions, deletions, and / or insertions from a reference VL sequence of SEQ ID NO: 9; and the protein binds ActRIIB; (d) the VH sequence has a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, less than 15, or 0 amino acid substitutions, deletions, and / or insertions from a reference VH sequence of SEQ ID NO: 22; and the VL sequence has a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, less than 15, or 0 amino acid substitutions, deletions, and / or insertions from a reference VL sequence of SEQ ID NO: 9; and the protein binds to ActRIIB; (e) the VH sequence has a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, less than 15, or 0 amino acid substitutions, deletions, and / or insertions from a reference VH sequence of SEQ ID NO: 28; and the VL sequence has a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, less than 15, or 0 amino acid substitutions, deletions, and / or insertions from a reference VL sequence of SEQ ID NO: 9; and the protein binds ActRIIB; (f) the VH sequence has a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15 or less, or 0 amino acid substitutions, deletions, and / or insertions from a reference VH sequence of SEQ ID NO: 34; and the VL sequence has a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15 or less, or 0 amino acid substitutions, deletions, and / or insertions from a reference VL sequence of SEQ ID NO: 9; and the protein binds ActRIIB; (g) the VH sequence has a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, less than 15, or 0 amino acid substitutions, deletions, and / or insertions from a reference VH sequence of SEQ ID NO: 40; and the VL sequence has a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, less than 15, or 0 amino acid substitutions, deletions, and / or insertions from a reference VL sequence of SEQ ID NO: 9; and the protein binds ActRIIB; (h) the VH sequence has a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, less than 15, or 0 amino acid substitutions, deletions, and / or insertions from a reference VH sequence of SEQ ID NO: 45; and the VL sequence has a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, less than 15, or 0 amino acid substitutions, deletions, and / or insertions from a reference VL sequence of SEQ ID NO: 50; and the protein binds ActRIIB; (i) the VH sequence has a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, less than 15, or 0 amino acid substitutions, deletions, and / or insertions from a reference VH sequence of SEQ ID NO: 57; and the VL sequence has a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, less than 15, or 0 amino acid substitutions, deletions, and / or insertions from a reference VL sequence of SEQ ID NO: 50; and the protein binds to ActRIIB; (j) the VH sequence has a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15 or less, or 0 amino acid substitutions, deletions, and / or insertions from a reference VH sequence of SEQ ID NO: 63; and the VL sequence has a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15 or less, or 0 amino acid substitutions, deletions, and / or insertions from a reference VL sequence of SEQ ID NO: 70; and the protein binds ActRIIB; (k) the VH sequence has a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15 or less, or 0 amino acid substitutions, deletions, and / or insertions from a reference VH sequence of SEQ ID NO: 77; and the VL sequence has a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15 or less, or 0 amino acid substitutions, deletions, and / or insertions from a reference VL sequence of SEQ ID NO: 70; and the protein binds ActRIIB; (l) the VH sequence has a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, less than 15, or 0 amino acid substitutions, deletions, and / or insertions from a reference VH sequence of SEQ ID NO: 144; and the VL sequence has a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, less than 15, or 0 amino acid substitutions, deletions, and / or insertions from a reference VL sequence of SEQ ID NO: 151; and the protein binds ActRIIB; (m) the VH sequence has a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, less than 15, or 0 amino acid substitutions, deletions, and / or insertions from a reference VH sequence of SEQ ID NO: 84; and the VL sequence has a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, less than 15, or 0 amino acid substitutions, deletions, and / or insertions from a reference VL sequence of SEQ ID NO: 91; and the protein binds ActRIIB and ActRIIA; (n) the VH sequence has a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, less than 15, or 0 amino acid substitutions, deletions, and / or insertions from a reference VH sequence of SEQ ID NO: 98; and the VL sequence has a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, less than 15, or 0 amino acid substitutions, deletions, and / or insertions from a reference VL sequence of SEQ ID NO: 91; wherein the protein binds ActRIIB and ActRIIA; (o) the VH sequence has a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, less than 15, or 0 amino acid substitutions, deletions, and / or insertions from the reference VH sequence of SEQ ID NO: 105; and the VL sequence has a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, less than 15, or 0 amino acid substitutions, deletions, and / or insertions from the reference VL sequence of SEQ ID NO: 91; and the protein binds ActRIIB and ActRIIA; (p) the VH sequence has a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, less than 15, or 0 amino acid substitutions, deletions, and / or insertions from the reference VH sequence of SEQ ID NO: 112; and the VL sequence has a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, less than 15, or 0 amino acid substitutions, deletions, and / or insertions from the reference VL sequence of SEQ ID NO: 91; and the protein binds ActRIIB and ActRIIA; (q) the VH sequence has a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, less than 15, or 0 amino acid substitutions, deletions, and / or insertions from a reference VH sequence of SEQ ID NO: 119; and the VL sequence has a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, less than 15, or 0 amino acid substitutions, deletions, and / or insertions from a reference VL sequence of SEQ ID NO: 91; and the protein binds ActRIIB and ActRIIA; or (r) the VH sequence has a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, less than 15, or 0 amino acid substitutions, deletions, and / or insertions from a reference VH sequence of SEQ ID NO: 125; and the VL sequence has a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, less than 15, or 0 amino acid substitutions, deletions, and / or insertions from a reference VL sequence of SEQ ID NO: 132; and the protein binds to ActRIIA. An ActRII binding protein comprising a VH and a VL.

12. (a) amino acid residues NANWELERT of ActRIIB (SEQ ID NO: 157); (b) amino acid residues CCEGNFCNER of ActRIIB (SEQ ID NO: 159); (c) amino acid residues CCEGNMCNEK (SEQ ID NO: 161) of ActRIIA; and (d) amino acid residues ECLFFNANWEKD of ActRIIA (SEQ ID NO: 162) An ActRII binding protein that binds to a polypeptide selected from the group consisting of:

13. An ActRII binding protein that binds to the same epitope as the ActRII binding protein of any one of claims 1-12.

14. An ActRII binding protein that competes with the ActRII binding protein of any one of claims 1 to 13 for binding to ActRII.

15. 15. The ActRII binding protein of any one of claims 1 to 14, wherein the ActRII binding protein antagonizes ActRII activity.

16. the binding protein (a) competing with activin A, activin B, BMP7, BMP9, BMP10, GDF8 (myostatin), GDF11, or Nodal for binding to ActRIIB and / or ActRIIA; (b) decreasing the phosphorylation of one or more Smads in cells expressing ActRIIB and / or ActRIIA in the presence of an ActRIIB or ActRIIA ligand (e.g., activin A); (c) decreasing the phosphorylation of ALK4 and / or ALK7 in cells expressing ActRIIB and / or ActRIIA and ALK4 and / or ALK7 in the presence of an ActRIIB and / or ActRIIA ligand; and (d) K of ≦1 nM and ≧1 pM Ｄ binding to ActRIIB and / or ActRIIA (e.g., as determined by BIACORE® analysis) 16. The ActRII binding protein of any one of claims 1 to 15, having at least one characteristic selected from the group consisting of:

17. 17. The ActRII binding protein of any one of claims 1 to 16, wherein the ActRII binding protein is an antibody that specifically binds to ActRII.

18. 18. The ActRII binding protein of claim 17, wherein the antibody is a monoclonal antibody, a recombinant antibody, a human antibody, a humanized antibody, a chimeric antibody, a bispecific antibody, a multispecific antibody, or an ActRII-binding antibody fragment.

19. The ActRII-binding antibody fragment may be a Fab fragment, a Fab' fragment, an F(ab') ２ 20. The ActRII binding protein of claim 18, which is selected from the group consisting of an antibody fragment, an Fv fragment, a diabody, or a single-chain antibody molecule.

20. The antibody (a) human IgA constant domain; (b) human IgD constant domain; (c) human IgE constant domain; (d) a human IgG1 constant domain; (e) a human IgG2 constant domain; (f) a human IgG3 constant domain; (g) a human IgG4 constant domain; and (h) human IgM constant domain 20. The ActRII binding protein of any one of claims 17 to 19, further comprising a heavy chain immunoglobulin constant domain selected from the group consisting of:

21. The antibody (a) a human Ig kappa constant domain; and (b) human Ig lambda constant domain 21. The ActRII binding protein of any one of claims 17 to 20, further comprising a light chain immunoglobulin constant domain selected from the group consisting of:

22. 22. The ActRII binding protein of any one of claims 17-21, wherein the antibody further comprises a human IgG1 heavy chain constant domain and a human lambda light chain constant domain.

23. 23. An isolated nucleic acid molecule or set of nucleic acid molecules encoding an ActRII binding protein of any one of claims 1 to 22.

24. 24. The isolated nucleic acid molecule or set of nucleic acid molecules of claim 23, which is cDNA.

25. 24. An isolated polynucleotide or cDNA molecule sufficient for use as a hybridization probe, PCR primer, or sequencing primer that is a fragment of the nucleic acid molecule or set of nucleic acid molecules of claim 22 or 23, or its complement.

26. 30. The nucleic acid or cDNA molecule of claim 22, 23, or 29, wherein the nucleic acid molecule is operably linked to a regulatory sequence.

27. A vector comprising the nucleic acid molecule of claim 22, 24, or 25.

28. A host cell comprising a nucleic acid molecule according to claim 22, 24 or 25, or a vector according to claim 31.

29. 28. The host cell of claim 27, wherein the host cell is a mammalian host cell.

30. 29. The mammalian host cell of claim 28, wherein the host cell is an NS0 mouse myeloma cell, a PER.C6® human cell, or a Chinese hamster ovary (CHO) cell.

31. 30. A method of making the ActRII binding protein of any one of claims 1 to 21, comprising culturing a host cell of claim 27, 28, or 29 under conditions suitable for producing said ActRII binding protein.

32. 31. The method of claim 30, further comprising isolating the secreted ActRII binding protein from the host cell.

33. 32. An ActRII binding protein produced using the method of claim 30 or 31.

34. 22. A pharmaceutical composition comprising an ActRII binding protein of any one of claims 1 to 20 or 21 and a pharmaceutically acceptable carrier.

35. 34. The pharmaceutical composition of claim 33 for use as a medicament.

36. 35. Use of the pharmaceutical composition of claim 34 to treat and / or ameliorate a disease or condition associated with ActRII expression or elevated ActRII signaling.

37. 36. The use of claim 35, wherein the disease or condition is a member selected from the group consisting of degenerative muscle diseases, muscular dystrophy, muscle atrophy, muscle wasting, fibrotic conditions (including hepatic, pulmonary, vascular, or ocular fibrotic conditions), myocardial fibrosis, idiopathic pulmonary fibrosis, metabolic diseases, type II diabetes, obesity, inflammatory diseases, autoimmune diseases, eye diseases, age-related macular degeneration, cardiovascular diseases, congestive heart failure, hypertension, pulmonary diseases, musculoskeletal diseases, skeletal diseases, osteoporosis, neuromuscular diseases, degenerative diseases, wound healing, and cancer.

38. 34. The pharmaceutical composition of claim 33, further comprising a labeling group or an effector group.

39. 38. The pharmaceutical composition of claim 37, wherein the effector group is selected from the group consisting of a radioisotope, a radionuclide, a toxin, a therapeutic agent, and a chemotherapeutic agent.

40. A method of treating and / or ameliorating a disease or condition associated with ActRII expression or elevated ActRII-mediated signaling, comprising administering to a subject in need thereof an effective amount of a composition comprising an ActRII binding protein of any one of claims 1 to 20 or 21, or a pharmaceutical composition of claim 33.

41. 40. The method of claim 39, wherein the disease or condition is a member selected from the group consisting of degenerative muscle diseases, muscular dystrophy, muscle atrophy, muscle wasting, fibrotic conditions (hepatic, pulmonary, vascular, or ocular fibrotic conditions), myocardial fibrosis, idiopathic pulmonary fibrosis, metabolic diseases, type II diabetes, obesity, inflammatory diseases, autoimmune diseases, ocular diseases, age-related macular degeneration, cardiovascular diseases, congestive heart failure, hypertension, pulmonary diseases, musculoskeletal diseases, skeletal diseases, osteoporosis, neuromuscular diseases, degenerative diseases, wound healing, and cancer.

42. 41. The method of claim 40, wherein the ActRII binding protein or pharmaceutical composition is administered alone or in combination therapy.

43. 44. A method of reducing ActRII activity in a subject comprising administering an effective amount of an ActRII binding protein of any one of claims 1-21 or 37, or a pharmaceutical composition of claim 39, 42, or 43.

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